Tricyclic and tetracyclic taxane intermediates

ABSTRACT

The synthesis of taxol and other tricyclic and tetracyclic taxanes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application based on U.S. Ser. No.09/333,382, filed Jun. 15, 1999, now U.S. Pat. No. 6,278,026, which is adivisional application based on U.S. Ser. No. 08/778,173, filed Jan. 2,1997, now U.S. Pat. No. 6,005,120, which is a divisional application ofU.S. Ser. No. 08/383,775 filed Feb. 6, 1995, now U.S. Pat. No.5,637,732, which is a divisional and continuation-in-part of applicationSer. No. 08/189,058, filed Jan. 27, 1994, now U.S. Pat. No. 5,405,972,which is a continuation-in-part of application Ser. No. 08/138,229,filed Oct. 15, 1993, now abandoned, which is a continuation-in-part ofapplication Ser. No. 08/095,161, filed Jul. 20, 1993, now abandoned.Said U.S. Pat. Nos. 5,637,732 and 6,005,120 are bothcontinuation-in-parts of PCT/US94/08350, filed Jul. 20, 1994.

This invention was made with Government support under NIH Grant #CA42031 and NIH Grant #CA 55131 awarded by the National Institutes ofHealth. The Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

The present invention is directed to the synthesis of taxol and othertricyclic and tetracyclic taxanes and novel intermediates thereof.

The taxane family of terpenes, of which taxol is a member, has attractedconsiderable interest in both the biological and chemical arts. Taxol isa promising cancer chemotherapeutic agent with a broad spectrum ofantileukemic and tumor-inhibiting activity. Taxol has the followingstructure:

wherein Ac is acetyl.

The supply of taxol is presently being provided by the bark from Taxusbrevifollia (Western Yew). However, taxol is found only in minutequantities in the bark of these slow growing evergreens. Consequently,chemists in recent years have expended their energies in trying to finda viable synthetic route for the preparation of taxol. To date, theresults have not been entirely satisfactory.

A semi-synthetic approach to the preparation of taxol has been describedby Greene, et al. in JACS 110, 5917 (1988), and involves the use of acongener of taxol, 10-deacetyl baccatin III which has the structure offormula II shown below:

10-deacetyl baccatin III is more readily available than taxol since itcan be obtained from the needles of Taxus baccata. According to themethod of Greene et al., 10-deacetyl baccatin III (“10-DAB”) isconverted to taxol by attachment of the C-10 acetyl group and byattachment of the C-13 β-amido ester side chain through theesterification of the C-13 alcohol with a β-amido carboxylic acid unit.

Denis et al. in U.S Pat. No. 4,924,011 disclose another process forpreparing derivatives of baccatin III or of 10-deacetylbaccatin III ofgeneral formula

in which R′ denotes hydrogen or acetyl. As reported, an acid of generalformula:

in which R₁ is a hydroxy-protecting group, is condensed with a taxanederivative of general formula:

in which R₂ is an acetyl hydroxy-protecting group and R₃ is ahydroxy-protecting group, and the protecting groups R₁, R₃ and, whereappropriate, R₂ are then replaced by hydrogen.

Other semisynthetic approaches for the preparation of taxol and for thepreparation of other taxanes which possess tumor-inhibiting propertieshave been reported in recent years, but each of these approachesrequires 10-DAB or baccatin III as a starting material. As such, thesupply of taxol and other taxane derivatives remains dependent at leastto some extent upon the collection of various parts of plants from theremote corners of the world and the extraction of 10-DAB and/or baccatinIII therefrom.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof a process for the synthesis of taxol and other tetracyclic taxanes;the provision of such a process which is highly diastereoselective; theprovision of such a process which proceeds in relatively high yield; andthe provision of key intermediates and processes for their preparation.

Briefly, therefore, the present invention is directed to a process forthe preparation of taxol and other tricyclic and tetracyclic taxanes.

In accordance with one aspect of the present invention, the processcomprises reacting a compound having the formula

with BrMgN(iPr)₂, an aldehyde (or ketone), followed by phosgene and analcohol to form a compound having the formula:

wherein

R₁ is hydrogen or protected hydroxy; R₂ is hydrogen or protectedhydroxy;

R₃ is oxo;

R_(7b) is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or—OCOR₃₆;

R_(7c) and R_(7d) are independently hydrogen, alkyl, alkenyl, alkynyl,aryl or heteroaryl;

R₉ is hydrogen, protected hydroxy, or oxo;

R₁₀ is —OP₁₀;

R₁₃ is —OP₁₃;

R₃₆ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀,—SX₁₀, monocyclic aryl or monocyclic heteroaryl;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

P₁₀ and P₁₃ are hydroxy protecting groups.

In accordance with another aspect of the present invention, the processcomprises reacting a compound having the formula

with lithium tetramethylpiperidide to form a compound having theformula:

wherein

R₁ is hydrogen or protected hydroxy;

R_(7c), is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R₉ is hydrogen, protected hydroxy, or oxo; and

P₁₀ and P₁₃ are hydroxy protecting groups.

In accordance with another aspect of the present invention, the processcomprises reacting a compound having the formula:

with lithium tetramethylpiperidide and camphosulfonyl oxaziridine toform a compound having the formula:

wherein R₉ is hydrogen, protected hydroxy, or oxo; R_(7c) is hydrogen,alkyl, alkenyl, alkynyl, aryl or heteroaryl; and P₁₀ and P₁₃ are hydroxyprotecting groups.

In accordance with another aspect of the present invention, the processcomprises reacting a compound having the formula:

with a hydride reducing agent, preferably Red-Al, to form a compoundhaving the formula:

wherein R₉ is hydrogen, protected hydroxy, or oxo; R_(7c) is hydrogen,alkyl, alkenyl, alkynyl, aryl or heteroaryl; and P₁₀ and P₁₃ are hydroxyprotecting groups.

In accordance with another aspect of the present invention, the processcomprises reacting a compound having the formula:

with lithium diisopropylamide to form a compound having the formula:

wherein R is lower alkyl, R₁ is hydrogen, protected hydroxy or R₁ and R₂together form a carbonate, R₂ is hydrogen, protected hydroxy or R₁ andR₂ together form a carbonate, R₉ is hydrogen, protected hydroxy, or oxo;and P₁₀ and P₁₃ are hydroxy protecting groups.

In accordance with another aspect of the present invention, the processcomprises reacting a compound having the formula:

with DBU to form a compound having the formula:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, or together withR₂ is a carbonate;

R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, or togetherwith R₁ is a carbonate;

R_(4a) is hydrogen, alkyl, hydroxy, or protected hydroxy, or togetherwith R₂ is a carbonate;

R_(4b) is hydroxymethylene;

R₅ is —OMs, —OTs or a bromide;

R_(7a) is hydrogen, protected hydroxy, or —OCOR₃₄, or together with R₉is a carbonate;

R₉ is hydrogen, oxo, hydroxy, protected hydroxy, or —OCOR₃₃, or togetherwith R_(7a) or R₁₀ is a carbonate;

R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy, or —OCOR₂₉, ortogether with R₉ is a carbonate;

P₁₃ is a hydroxy protecting group;

R₂₉, R₃₀, R₃₁, R₃₃ and R₃₄ are independently hydrogen, alkyl, alkenyl,alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl or monocyclicheteroaryl;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.

In accordance with another aspect of the present invention, the processcomprises reacting a compound having the formula:

with KOtBu and (PhSeO)₂O to form a compound having the formula:

which rearranges in the presence of additional KOtBu, silica gel, orother acids or bases, or with heat to a compound having the formula:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy, or —OCOR₃₀, or together withR₂ is a carbonate;

R₂ is hydrogen, protected hydroxy, or —OCOR₃₁, or together with R₁ orR_(4a) is a carbonate;

R_(4a) is hydrogen, alkyl, hydroxy, protected hydroxy, or —OCOR₂₇,together with R_(4b) is an oxo, or together with R₂, R_(4b), or R₅ is acarbonate;

R_(4b) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or cyano,together with R_(4a) is an oxo, together with R_(4a) or R₅ is acarbonate, or together with R₅ and the carbons to which they areattached form an oxetane ring;

R₅ is hydrogen, protected hydroxy, —OCOR₃₇, together with R_(4a) orR_(4b) is a carbonate, or together with R_(4b) and the carbons to whichthey are attached form an oxetane ring;

R_(7a) is hydrogen, halogen, protected hydroxy, or —OCOR₃₄;

P₁₃ is a hydroxy protecting group;

R₂₇, R₃₀, R₃₁, R₃₄ and R₃₇ are independently hydrogen, alkyl, alkenyl,alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl or monocyclicheteroaryl;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; and

X₁₀ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstitutedalkyl, alkenyl alkynyl, aryl or heteroaryl.

In general, the process of the present invention may be used to preparetaxanes having the formula:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy, or —OCOR₃₀;

R₂ is hydrogen, hydroxy, —OCOR₃₁, or oxo;

R_(4a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano,hydroxy, —OCOR₂₇, or together with R_(4b) forms an oxo, oxirane ormethylene;

R_(4b) is hydrogen, together with R_(4a) forms an oxo, oxirane ormethylene, or together with R₅ and the carbon atoms to which they areattached form an oxetane ring;

R₅ is hydrogen, halogen, hydroxy, protected hydroxy, —OCOR₃₇, oxo, ortogether with R_(4b) and the carbon atoms to which they are attachedform an oxetane ring;

R₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy,protected hydroxy or together with R_(6a) forms an oxo;

R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy,protected hydroxy or together with R₆ forms an oxo;

R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OCOR₃₄, oxo,or —OR₂₈;

R₉ is hydrogen, hydroxy, protected hydroxy, acyloxy, or oxo;

R₁₀ is hydrogen, —OCOR₂₉, hydroxy, protected hydroxy, or oxo;

R₁₃ is hydroxy, protected hydroxy, MO— or

R₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

R_(14a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl,hydroxy, protected hydroxy or together with R₁ forms a carbonate;

R₂₈ is a functional group which increases the solubility of the taxane;

R₂₇, R₂₉, R₃₀, R₃₁, R₃₄ and R₃₇ are independently hydrogen, alkyl,alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl;

X₁ is —OX₆, —SX₇, or —NX₈X₉;

X₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₃ and X₄ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl;

X₅ is —COX₁₀, —COOX₁₀, —COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁;

X₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyprotecting group, or a functional group which increases the watersolubility of the taxane derivative;

X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;

X₉ is an amino protecting group;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstitutedalkyl, alkenyl alkynyl, aryl or heteroaryl;

X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OX₁₀, or —NX₈X₁₄;

X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

M comprises ammonium or is a metal.

The present invention is additionally directed to an intermediate foruse in the preparation of a tricyclic or tetracyclic taxane having theformula:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR ₃₀, or together withR₂ is a carbonate;

R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, or togetherwith R₁ is a carbonate;

R₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₂, or oxo;

R₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R₉ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₃, or togetherwith R₁₀ is a carbonate;

R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉, ortogether with R₉ is a carbonate;

R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₅ are independently hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₉, monocyclic aryl ormonocyclic heteroaryl;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

M comprises ammonium or is a metal.

The present invention is further directed to an intermediate for use inthe preparation of a tricyclic or tetracyclic taxane having the formula:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, or together withR₂ is a carbonate;

R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, or togetherwith R₁ is a carbonate;

R₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₂, or oxo, or togetherwith R_(7b) is a carbonate;

R_(7b) is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or—OCOR₃₆, or together with R₃ or R₉ is a carbonate;

R_(7c) and R_(7d) are independently hydrogen, alkyl, alkenyl, alkynyl,aryl or heteroaryl;

R₉ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₃, or togetherwith R_(7b) or R₁₀ is a carbonate;

R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉, ortogether with R₉ is a carbonate;

R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₅ and R₃₆ are independently hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl ormonocyclic heteroaryl;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

M comprises ammonium or is a metal.

The invention is further directed to an intermediate for use in thepreparation of a tricyclic or tetracyclic taxane having the formula:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, or together withR₂ is a carbonate;

R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, or togetherwith R₁ is a carbonate;

R₃ is hydrogen, hydroxy, protected hydroxy, or —OCOR₃₂;

R_(7b) is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or—OCOR₃₆;

R_(7c) is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;

R₉ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₃, or togetherwith R₁₀ is a carbonate;

R₁₀ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₂₉, ortogether with R₉ is a carbonate;

R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₅ and R₃₆ are independently hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl ormonocyclic heteroaryl;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

M comprises ammonium or is a metal.

The present invention is further directed to an intermediate for use inthe preparation of a tricyclic or tetracyclic taxane having the formula:

wherein

R is C₁-C₈ alkyl,

R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, or together withR₂ is a carbonate;

R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, togetherwith R₁ is a carbonate, or together with R₄ is a carbonate;

R_(4a) is hydrogen, alkyl, hydroxy, protected hydroxy, or —OCOR₂₇, ortogether with R₂ is a carbonate;

R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OR₂₈, —OCOR₃₄,or together with R₉ is a carbonate;

R₉ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or —OCOR₃₃, ortogether with R_(7a) or R₁₀ is a carbonate;

R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or —OCOR₂₉, ortogether with R₉ is a carbonate;

R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅ or MO—;

R₂₈ is a functional group which increases the solubility of the taxanederivative;

R₂₇, R₂₉, R₃₀, R₃₁, R₃₃, R₃₄, and R₃₅ are independently hydrogen, alkyl,alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl ormonocyclic heteroaryl;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

M comprises ammonium or is a metal.

The invention is further directed to an intermediate for use in thepreparation of a tricyclic or tetracyclic taxane having the formula:

wherein

R₁ is hydrogen, hydroxy, protected hydroxy or —OCOR₃₀, or together withR₂ is a carbonate;

R₂ is hydrogen, hydroxy, protected hydroxy, oxo, or —OCOR₃₁, or togetherwith R₁ or R_(4a) is a carbonate;

R_(4a) is hydrogen, alkyl, hydroxy, protected hydroxy, or —OCOR₂₇,together with R_(4b) is an oxo, or together with R₂, R_(4b), or R₅ is acarbonate;

R_(4b) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or cyano,together with R_(4a) is an oxo, together with R_(4a) or R₅ is acarbonate, or together with R₅ and the carbons to which they areattached form an oxetane ring;

R₅ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₇, oxo, together withR_(4a) or R_(4b) is a carbonate, or together with R_(4b) and the carbonsto which they are attached form an oxetane ring;

R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OR₂₈, or—OCOR₃₄, or together with R₉ is a carbonate;

R₉ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or —OCOR₃₃, ortogether with R_(7a) or R₁₀ is a carbonate;

R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy, —OR₂₈, or —OCOR₂₉, ortogether with R₉ is a carbonate;

R₁₃ is hydrogen, hydroxy, protected hydroxy, —OCOR₃₅, MO— or

R₂₈ is a functional group which increases the solubility of the taxanederivative;

R₂₇, R₂₈, R₃₀, R₃₁, R₃₃, R₃₄, R₃₅ and R₃₇ are independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclicaryl or monocyclic heteroaryl;

X₁ is —OX₆, —SX₇, or —NX₈X₉;

X₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₃ and X₄ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl;

X₅ is —COX₁₀, —COOX₁₀, —COSX₁₀, —CONX₈X₁₀, or —SO₂X₁₁;

X₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyprotecting group, or a functional group which increases the watersolubility of the taxane derivative;

X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₉ is an amino protecting group;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OX₁₀, or —NX₈X₁₄;

X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and

M comprises ammonium or is a metal.

The present invention is additionally directed to compounds having theformulae

wherein

R is lower alkyl,

T₄ is hydroxy or protected hydroxy,

T_(4a) and T_(4b) are independently alkoxy, alkoxycarbonyloxy, acyloxy,sulfonyloxy, hydroxy, or protected hydroxy, or together form acarbonate,

T₅ is alkoxy, alkoxycarbonyloxy, acyloxy, sulfonyloxy, hydroxy, orprotected hydroxy,

P₅, P₇, P₁₀ and P₁₃ are hydroxy protecting groups, and

R₂, R_(4a), R_(7a), R_(10a), and R₁₃ are as previously defined. Thesecompounds are key intermediates in the synthesis of taxol and othertaxanes. The present invention is also directed to processes for thepreparation of these key intermediates.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein “Ar” means aryl; “Ph” means phenyl; “Me” means methyl;“Et” means ethyl; “iPr” means isopropyl; “tBu” and “t-Bu” meanstert-butyl; “R” means lower alkyl unless otherwise defined; “Ac” meansacetyl; “py” means pyridine; “TES” means triethylsilyl; “TMS” meanstrimethylsilyl; “TBS” means Me₂t-BuSi-; “Tf” means —SO₂CF₃; “BMDA” meansBrMgNiPr₂; “Swern” means (COCl)₂, Et₃N; “LTMP” means lithiumtetramethylpiperidide; “MOP” means 2-methoxy-2-propyl; “BOM” meansbenzyloxymethyl; “LDA” means lithium diisopropylamide; “LAH” meanslithium aluminum hydride; “Red-Al” means sodium bis(2-methoxyethoxy)aluminum hydride; “Ms” means CH₃SO₂—; “TASF” meanstris(diethylamino)sulfonium-difluorotrimethylsilicate; “Ts” meanstoluenesulfonyl; “TBAF” means tetrabutyl ammonium fluoride; “TPAP” meanstetrapropyl-ammonium perruthenate; “DBU” means diazabicycloundecane;“DMAP” means p-dimethylamino pyridine; “LHMDS” means lithiumhexamethyldisilazide; “DMF” means dimethylformamide; “AIBN” meansazo-(bis)-isobutyronitrile; “10-DAB” means 10-desacetylbaccatin III;“FAR” means 2-chloro-1,1,2-trifluorotriethylamine; “mCPBA” meansmetachloroperbenzoic acid; “DDQ” means dicyanodichloroquinone;“sulfhydryl protecting group” includes, but is not limited to,hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, orthiocarbonates; “amine protecting group” includes, but is not limitedto, carbamates, for example, 2,2,2,-trichloroethylcarbamate ortertbutylcarbamate; “protected hydroxy” means —OP wherein P is a hydroxyprotecting group; and “hydroxy protecting group” includes, but is notlimited to, acetals having two to ten carbons, ketals having two to tencarbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl,p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl,ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilylethers such as trimethylsilyl ether, triethylsilyl ether,dimethylarylsilyl ether, triisopropylsilyl ether andt-butyldimethylsilyl ether; esters such as benzoyl, acetyl,phenylacetyl, formyl, mono-, di-, and trihaloacetyl such aschloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl; andcarbonates including but not limited to alkyl carbonates having from oneto six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to sixcarbon atoms and substituted with one or more halogen atoms such as2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenyl carbonateshaving from two to six carbon atoms such as vinyl and allyl; cycloalkylcarbonates having from three to six carbon atoms such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonatesoptionally substituted on the ring with one or more C₁₋₆ alkoxy, ornitro. Other hydroxyl, sulfhydryl and amine protecting groups may befound in “Protective Groups in Organic Synthesis” by T. W. Greene, JohnWiley and Sons, 1981.

The alkyl groups described herein are preferably lower alkyl containingfrom one to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be straight or branched chain and include methyl, ethyl,propyl, isopropyl, butyl, hexyl and the like. They may be hydrocarbon orheterosubstituted with the various substituents defined herein,including heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl,aryl, heteroaryl, and heterosubstituted heteroaryl.

The alkenyl groups described herein are preferably lower alkenylcontaining from two to six carbon atoms in the principal chain and up to15 carbon atoms. They may be straight or branched chain and includeethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and thelike. They may be hydrocarbon or heterosubstituted with the varioussubstituents defined herein, including alkyl, heteroalkyl,heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, andheterosubstituted heteroaryl.

The alkynyl groups described herein are preferably lower alkynylcontaining from two to six carbon atoms in the principal chain and up to15 carbon atoms. They may be straight or branched chain and includeethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They maybe hydrocarbon or heterosubstituted with the various substituentsdefined herein, including alkyl, heteroalkyl, alkenyl, heteroalkenyl,heteroalkynyl, aryl, heteroaryl, and heterosubstituted heteroaryl.

The aryl moieties described herein contain from 6 to 15 carbon atoms andinclude phenyl. They may be hydrocarbon or heterosubstituted with thevarious substituents defined herein, including alkyl, heteroalkyl,alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, heteroaryl, andheterosubstituted heteroaryl. Phenyl is the more preferred aryl.

The heteroaryl moieties described herein contain from 5 to 15 atoms andinclude, furyl, thienyl, pyridyl and the like. They may be hydrocarbonor heterosubstituted with the various substituents defined herein,including alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,heteroalkynyl, aryl, and heterosubstituted heteroaryl.

The acyl moieties described herein contain alkyl, alkenyl, alkynyl, arylor heteroaryl groups.

The alkoxycarbonyloxy moieties described herein comprise lower alkyl,alkenyl, alkynyl or aryl groups.

The hydrocarbon substituents described herein may be alkyl, alkenyl,alkynyl, or aryl, and the heterosubstituents of the heterosubstitutedalkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties described hereincontain nitrogen, oxygen, sulfur, halogens and/or one to six carbons,and include lower alkoxy such as methoxy, ethoxy, butoxy, halogen suchas chloro or fluoro, and nitro, heteroaryl such as furyl or thienyl,alkanoxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, andamido.

An exemplary synthesis of baccatin III or 10-DAB is depicted hereinbelowin Reaction Scheme A. The starting material, diol 2, can be preparedfrom patchino (commonly known as B-patchouline epoxide) which iscommercially available. The patchino is first reacted with anorgano-metallic, such as lithium t-butyl followed by oxidation with anorganic peroxide, such as t-butylperoxide in the presence of titaniumtetraisopropoxide to form a tertiary alcohol. The tertiary alcohol isthen reacted with a Lewis acid, such as boron trifluoride at lowtemperature, in the range from 40° C. to −100° C.; in the presence of anacid, such as trifluoromethane sulfonic acid. A graphical depiction ofthis reaction scheme along with an experimental write-up for thepreparation of diol 2 can be found in U.S. Pat. No. 4,876,399.

In Reaction Scheme A, P₅ is TMS, P₇ is MOP or BOM, P₁₀ is TES, P₁₃ isTBS, and R is ethyl in compounds 6 and 7, methyl in compounds 15, 16,and 17, Ms in compounds 24aa and 26a, and Ts in compound 26aa. It shouldbe understood, however, that P₅, P₇, P₁₀, and P₁₃ may be other hydroxyprotecting groups and R may comprise other lower alkyl substituents incompounds 6, 7, 15, 16 and 17.

Reaction Scheme A may be varied between compounds 18 and 29 as set forthbelow in Reaction Scheme A′, with the reactions leading to compound 18and following compound 29 being as set forth in Reaction Scheme A.

In Reaction Scheme A′, P₅ is TMS or Ac, P₇ is MOP or BOM, P₁₀ is TES,P₁₃ is TBS and P₅₂₀ is acetal or ketal, preferably acetonide. It shouldbe understood, however, that P₅, P₇, P₁₀, and P₁₃ and P₅₂₀ may be otherhydroxy protecting groups.

In general, tricyclic and tetracyclic taxanes bearing C13 side chainsmay be obtained by reacting a β-lactam with alkoxides having the taxanetricyclic or tetracyclic nucleus and a C-13 metallic oxide substituentto form compounds having a β-amido ester substituent at C-13. Theβ-lactams have the following structural formula:

wherein X₁-X₅ are as defined above. The alkoxides having the tricyclicor tetracyclic taxane nucleus and a C-13 metallic oxide or ammoniumoxide substituent have the following structural formula:

wherein R₁, R₂, R_(4a), R_(4b), R₅, R₆, R_(6a), R_(7a), R₉, R₁₀, R₁₄,and R_(14a) are as previously defined, R₁₃ is —OM and M comprisesammonium or is a metal optionally selected from Group IA, IIA,transition (including lanthanides and actinides), IIB, IIIA IVA, VA, orVIA metals (CAS version). If M comprises ammonium, it is preferablytetraalkylammonium and the alkyl component of the tetraalkylanmoniumsubstituent is preferably C₁—C₁₀ alkyl such as methyl or butyl. Mostpreferably, the alkoxide has the tetracyclic taxane nucleus andcorresponds to the structural formula:

wherein M, R₂, R_(4a), R_(7a), R₉, and R₁₀ are as previously defined.

As set forth in Reaction Scheme A, taxol may be prepared by converting7-protected Baccatin III 35 to the corresponding alkoxide and reactingthe alkoxide with a β-lactam in which X₁ is protected hydroxy, X₃ isphenyl and X₅ is benzoyl. Protecting groups such as 2-methoxypropyl(“MOP”), 1-ethoxyethyl (“EE”) are preferred, but a variety of otherstandard protecting groups such as the triethylsilyl group or othertrialkyl (or aryl) silyl groups may be used. Taxanes having alternativeside chain substituents may be prepared through the use of β-lactamswhich comprise the alternative substituents.

Taxanes having alternative C9 substituents may be prepared byselectively reducing the C9 keto substituent of taxol, 10-DAB, BaccatinIII or one of the other intermediates disclosed herein to yield thecorresponding C9 β-hydroxy derivative. The reducing agent is preferablya borohydride and, most preferably, tetrabutylammoniumboro-hydride(Bu₄NBH₄) or triacetoxyborohydride.

As illustrated in Reaction Scheme 1, the reaction of baccatin III withBu₄NBH₄ in methylene chloride yields 9-desoxo-9β-hydroxybaccatin III 5.After the C7 hydroxy group is protected with the triethylsilylprotecting group, for example, a suitable side chain may be attached to7-protected-9β-hydroxy derivative 6 as elsewhere described herein.Removal of the remaining protecting groups thus yields 9β-hydroxy-desoxotaxol or other 9β-hydroxytetracylic taxane having a C13 side chain.

Alternatively, the C13 hydroxy group of 7-protected-9β-hydroxyderivative 6 may be protected with trimethylsilyl or other protectinggroup which can be selectively removed relative to the C7 hydroxyprotecting group as illustrated in Reaction Scheme 2, to enable furtherselective manipulation of the various substituents of the taxane. Forexample, reaction of 7,13-protected-9β-hydroxy derivative 7 with KHcauses the acetate group to migrate from C10 to C9 and the hydroxy groupto migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8.Protection of the C10 hydroxy group of 10-desacetyl derivative 8 withtriethylsilyl yields derivative 9. Selective removal of the C13 hydroxyprotecting group from derivative 9 yields derivative 10 to which asuitable side chain may be attached as described above.

As shown in Reaction Scheme 3, 10-oxo derivative 11 can be provided byoxidation of 10-desacetyl derivative 8. Thereafter, the C13 hydroxyprotecting group can be selectively removed followed by attachment of aside chain as described above to yield 9-acetoxy-10-oxo-taxol or other9-acetoxy-10-oxotetracylic taxanes having a C13 side chain.Alternatively, the C9 acetate group can be selectively removed byreduction of 10-oxo derivative 11 with a reducing agent such as samariumdiiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13hydroxy protecting group can be selectively removed followed byattachment of a side chain as described above to yield9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes havinga C13 side chain.

Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced toyield pentaol 13. The C7 and C10 hydroxyl groups of pentaol 13 can thenbe selectively protected with the triethylsilyl or another protectinggroup to produce triol 14 to which a C13 side chain can be attached asdescribed above or, alternatively, after further modification of thetetracylic substituents.

Taxanes having C9 and/or C10 acyloxy substituents other than acetate canbe prepared using 10-DAB as a starting material as illustrated inReaction Scheme 5. Reaction of 10-DAB with triethylsilyl chloride inpyridine yields 7-protected 10-DAB 15. The C10 hydroxy substituent of7-protected 10-DAB 15 may then be readily acylated with any standardacylating agent to yield derivative 16 having a new C10 acyloxysubstituent. Selective reduction of the C9 keto substituent ofderivative 16 yields 9β-hydroxy derivative 17 to which a C13 side chainmay be attached. Alternatively, the C10 and C9 groups can be caused tomigrate as set forth in Reaction Scheme 2, above.

Taxanes having alternative C2 and/or C4 esters can be prepared usingbaccatin III and 10-DAB as starting materials. The C2 and/or C4 estersof baccatin III and 10-DAB can be selectively reduced to thecorresponding alcohol(s) using reducing agents such as LAH or Red-Al,and new esters can thereafter be substituted using standard acylatingagents such as anhydrides and acid chlorides in combination with anamine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.Alternatively, the C2 and/or C4 alcohols may be converted to new C2and/or C4 esters through formation of the corresponding alkoxide bytreatment of the alcohol with a suitable base such as LDA followed by anacylating agent such as an acid chloride.

Baccatin III and 10-DAB analogs having different substituents at C2and/or C4 can be prepared as set forth in Reaction Schemes 6-10. Tosimplify the description, 10-DAB is used as the starting material. Itshould be understood, however, that baccatin III derivatives or analogsmay be produced using the same series of reactions (except for theprotection of the C10 hydroxy group) by simply replacing 10-DAB withbaccatin III as the starting material. 9-desoxo derivatives of thebaccatin III and 10-DAB analogs having different substituents at C2and/or C4 can then be prepared by reducing the C9 keto substituent ofthese analogs and carrying out the other reactions described above.

In Reaction Scheme 6, protected 10-DAB 3 is converted to the triol 18with lithium aluminum hydride. Triol 18 is then converted to thecorresponding C4 ester using Cl₂CO in pyridine followed by anucleophilic agent (e.g., Grignard reagents or alkyllithium reagents).

Deprotonation of triol 18 with LDA followed by introduction of an acidchloride selectively gives the C4 ester. For example, when acetylchloride was used, triol 18 was converted to 1,2 diol 4 as set forth inReaction Scheme 7.

Triol 18 can also readily be converted to the 1,2 carbonate 19.Acetylation of carbonate 19 under vigorous standard conditions providescarbonate 21 as described in Reaction Scheme 8; addition ofalkyllithiums or Grignard reagents to carbonate 19 provides the C2 esterhaving a free hydroxyl group at C4 as set forth in Reaction Scheme 6.

As set forth in Reaction Scheme 9, other C4 substituents can be providedby reacting carbonate 19 with an acid chloride and a tertiary amine toyield carbonate 22 which is then reacted with alkyllithiums or Grignardreagents to provide 10-DAB derivatives having new substituents at C2.

Alternatively, baccatin III may be used as a starting material andreacted as shown in Reaction Scheme 10. After being protected at C7 andC13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24.Tetraol 24 is converted to carbonate 25 using Cl₂CO and pyridine, andcarbonate 25 is acylated at C10 with an acid chloride and pyridine toproduce carbonate 26 (as shown) or with acetic anhydride and pyridine(not shown). Acetylation of carbonate 26 under vigorous standardconditions provides carbonate 27 which is then reacted with alkyllithiums to provide the baccatin III derivatives having new substituentsat C2 and C10.

10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of10-DAB may be prepared by reacting baccatin III or 10-DAB (or theirderivatives) with samarium diiodide. Reaction between the tetracyclictaxane having a C10 leaving group and samarium duiodide may be carriedout at 0° C. in a solvent such as tetrahydrofuran. Advantageously, thesamarium diiodide selectively abstracts the C10 leaving group; C13 sidechains and other substituents on the tetracyclic nucleus remainundisturbed. Thereafter, the C9 keto substituent may be reduced toprovide the corresponding 9-desoxo-9β-hydroxy-10-desacetyoxy or10-desoxy derivatives as otherwise described herein.

C7 dihydro and other C7 substituted taxanes can be prepared as set forthin Reaction Schemes 11, 12 and 12a.

As shown in Reaction Scheme 12, Baccatin III may be converted into7-fluoro baccatin III by treatment with FAR at room temperature in THFsolution. Other baccatin derivatives with a free C7 hydroxyl groupbehave similarly. Alternatively, 7-chloro baccatin III can be preparedby treatment of baccatin III with methane sulfonyl chloride andtriethylamine in methylene chloride solution containing an excess oftriethylamine hydrochloride.

Taxanes having C7 acyloxy-substituents can be prepared as set forth inReaction Scheme 12a, 7,13-protected 10-oxo-derivative 11 is converted toits corresponding C13 alkoxide by selectively removing the C13protecting group and replacing it with a metal such as lithium. Thealkoxide is then reacted with a P-lactam or other side chain precursor.Subsequent hydrolysis of the C7 protecting groups causes a migration ofthe C7 hydroxy substituent to C10, migration of the C10 oxo substituentto C9, and migration of the C9 acyloxy substituent to C7.

As shown in Reaction Scheme 13, 7-O-triethylsilyl baccatin III can beconverted to a tricyclic taxane through the action of trimethyloxoniumtetrafluoroborate in methylene chloride solution. The product diol thenreacts with lead tetraacetate to provide the corresponding C4 ketone.

The subprocesses of Reaction scheme A can be applied at various stages.For example, the process for the conversion of compound 30 to compound33 can be applied to any intermediate having a hydroxyl group at C-10and two hydrogens at C-9, e.g., the process for introducing C9 and C10carbonyl and hydroxyl groups can be applied to suitably protectedintermediates 4 through 29.

Likewise, the process for introduction of C1 and C2 oxygen-containingfunctional groups (conversion of 6 to 13 in Reaction Scheme A) can beapplied to any intermediate having a C3 carbonyl group.

Similarly, the process for introducing C2 and C4 acyl groups asexemplified in Reaction Schemes 6 through 10 can be applied to anyintermediate having a C1, C2 carbonate.

Also, the process for forming the oxetane ring, as exemplified in theconversion of 24a to 27a in Reaction Scheme A, can be applied to avariety of intermediates having a C4 carbonyl group.

The aldol process exemplified in the conversion of 5 to 6 in ReactionScheme A can be applied to any suitably protected intermediate having aC3 carbonyl group and a ε8a hydrogen. A variety of ketones or aldehydescan be used as a reactant in this process.

Formation of a cyclic carbonate from any 1,2 or 1,3 diol subunit in anyintermediate can be carried out by using phosgene as a reactant.Carbonyl groups can be reduced by hydride reagents or metallic speciesto the corresponding alcohols. Alcohols can be oxidized using a varietyof oxidizing agents as exemplified in the Reaction Schemes, to thecorresponding carbonyl groups.

The compounds disclosed in this application have several asymmetriccarbons and may exist in diastereomeric, racemic, or optically activeforms. All of these forms are contemplated within the scope of thisinvention. More specifically, the present invention includes theenantiomers, diasteriomers, racemic mixtures, and other mixtures of thecompounds disclosed herein.

The following examples illustrate the invention.

EXAMPLES Reaction Scheme A

Triethylsilyloxy alcohol 3. To a solution of diol 2 (3.16 g, 13.4 mmol)and DMAP (70 mg, 0.57 mmol) in CH₂Cl₂ (65 mL) at room temperature wasadded triethylamine (3.7 mL, 26.6 mmol) followed by dropwise addition ofTESCl (2.7 mL, 16.1 mmol). After 1.75 h, the reaction mixture wasdiluted with 150 mL of hexane, then poured into 100 mL of a saturatedaqueous NaHCO₃ solution and 150 mL of hexane. The organic phase waswashed with two 100 mL portions of saturated aqueous NaHCO₃ solution andwith 100 mL of water, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure to give 4.88 g of crude triethylsilyloxyalcohol3. An analytical sample was obtained by plug filtration through a shortpad of silica gel washing with hexane and then eluting the pure compound3 (P₁₀=TES) (colorless oil) with 5% ethyl acetate in hexane.

3 (P₁₀=TES): ¹H NMR (300 MHz, CDCl₃) δ 0.61 (q, J=7.7 Hz, 6H, TES CH₂),0.89 (s, 3H, CH₃ 16), 0.96 (t, J=7.7 Hz, 9H, TES CH₃), 1.03 (d, J=7.1Hz, 3H, CH₃ 19), 1.07 (s, 3H, CH₃ 17), 1.23 (d, J=14.3 Hz, 1H, H2α),1.56 (dd, J=6.0, 6.0 Hz, 1H, H7),.1.76 (ddd, J=5.0, 11.0, 13.7 Hz, 1H,H9), 1.90 (ddd, J=2.2, 8.8, 15.4 Hz, 1H, H9), 1.96 (m, 1H, H14α), 2.37(m, 2H, H2β, H14β), 2.51 (ddd, J=7.7, 7.7, 10.4 Hz, 1H, H8α), 2.94 (s,1H, OH-3), 4.21 (dd, J=2.2, 5.0 Hz, 1H, H10), 5.43 (dd, J=2.8, 2.8 Hz,1H, H13). ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 4.8 (TES CH₂), 6.7 (TES CH₃),15.02 (CH₃ 19), 23.0 (CH₃ 17), 26.2 (CH₃ 18), 28.0 (CH₃ 16), 33.6 (C14),41.5 (C8), 44.2 (C2), 45.0 (C1), 45.2 (C15), 45.8 (C9), 69.6 (C11), 74.9(C10), 96.0 (C3), 123.0 (C13), 143.7 (C12); IR (CHCl₃) υ 3530, 2970,2930, 2900, 1460, 1340, 1140, 1100, 1080, 1045, 1010, 970, 915, 650cm⁻¹; MS (CI) 351 (M+1, 58), 333 (100), 219 (34).

Hydroxy Ketone 4. To a vigorously stirred solution of the crude compound3 (P₁₀=TES) in anhydrous CH₂Cl₂ (30 mL) at 0° C. under nitrogen wasadded Ti (O^(i)Pr)₄ (13.5 mL, 43.1 mmol) followed by dropwise additionof anhydrous 2M ^(t)-BuOOH in hexane (18 mL, 36 mmol). After 45 mindimethylsulfide (15 mL) was added slowly over a period of 5 min. Thesolution was stirred for 10 min at 0° C., then 15 min at roomtemperature and then moved to a 55° C. bath where it was heated underreflux for 8h. The solvents were evaporated under reduced pressure, theresulting thick syrup was dissolved in ethyl acetate (850 mL) and 3.5 mLof H₂O was added dropwise with vigorous stirring. The resulting mixturewas stirred at room temperature for 1 h and then filtered through a padof Celite which was further washed with two protions of 100 mL of ethylacetate. Evaporation of the solvent under reduced pressure afforded anoil that was filtered through a short pad of silica gel eluting with 10%ethyl acetate in hexane to give 4.78 g of pure hydroxyketone 4 (P₁₀=TES)(colorless oil).

4 (P₁₀=TES): ¹H NMR (300 MHz, CDCl₃) δ 0.58 (q, J=7.7 Hz, 6H, TES CH₂),0.94 (t, J=7.7 Hz, 12H, CH₃ 19, TES CH₃), 0.98 (s, 3H, CH₃ 17), 1.31 (s,3H, CH₃ 16), 1.71 (dd, J=5.0, 11.5 Hz, 1H, H2α), 1.85 (m, 3H, H1, H9β,H14β), 1.96 (s, 3H, CH₃ 18), 2.15 (d, J=12.1, 1H, OH—13), 2.22 (ddd,J=4.9, 13.2, 15.9 Hz, 1H, H9α), 2.56 (dddd, J=3.8, 7.1, 13.7, 13.7 Hz,1H, H8α), 2.75 (dd, J=2.2, 11.0 Hz, 1H, H2β), 2.80 (ddd, J=4.4, 7.7,11.0 Hz, 1H, H14β), 4.10 (t, J=11.0 HZ, 1H, H13β), 4.56 (d, J=5.0 Hz,1H, H10β); ¹³C NMR (75 MHz, CDCl₃) δ (ppm) 4.3 (TES CH₂), 6.5 (TES CH₃),13.4 (CH₃ 18), 18.4 (CH₃19), 25.8 (CH₃ 17), 27.1 (CH₃ 16), 34.7 (C14),38.2 (C15), 38.8 (C2), 44.0 (C8), 44.2 (C9), 47.8 (C1), 67.3 (C13), 69.7(C10), 137.3 (C11), 138.8 (C12), 219.2 (C3); IR (CHCl₃) υ 3550, 2960,2880, 1660, 1460, 1410, 1240, 1200, 1160, 1140, 1080, 1050, 1000, 980,900, 810 cm⁻¹; MS (CI) 367 (M+1, 2), 349 (100), 331 (55).

Ketone 5. To a solution of hydroxyketone 4 (P₁₀=TES) in anhydrouspyridine (25 mL) at −23° C. under nitrogen was added dropwise TBSOTf(3.2 mL, 13.9 mmol). After 5 mnn, the flask was moved to an ice bath andstirred for 1.75 h. The solution was diluted with 75 mL of hexane at 0°C. and then decanted from the insoluble oil into saturated aqueousNaHCO₃ solution (200 mL). The remaining oil was extracted with three 75mL portions of hexane. The combined organic phases were washed with two50 mL portions of saturated aqueous NaHCO₃ solution and then with 50 mLof water, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The yellowish oily residue was purified by filtration througha short pad of silica gel eluting with 10% ethyl acetate in hexane togive 4.78 g of pure ketone 5 (P₁₀=TES, P₁₃=TBS) (94% yield from 2).

5 (P₁₀=TES, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 3H, TBS CH₃),0.05 (s, 3H, TBS CH₃), 0.57 (q, J=8.2 Hz, 6H, TES CH₂), 0.93 (t, J=8.2Hz, 9H, TES CH₃), 0.93 (s, 9H, TBS t-Bu), 0.96 (d, J=1.8 Hz, 3H, CH₃19), 1.06 (s, 3H, CH₃ 17), 1.33 (s, 3H, CH₃ 16), 1.68 (dd, J=5.5, 11.5Hz, 1H, H2α), 1.84 (m, 2H, H1, H9β), 1.89 (s, 3H, CH₃ 18), 1.92 (dd,J=6.0, 14.3 Hz, 1H, H14α), 2.21 (ddd, J=5.5, 13.2, 15.4 Hz, 1H, H9α),2.39 (ddd, J=8.2, 10.4, 14.3 Hz, 1H, H14β), 2.52 (ddd, J=3.9, 7.1, 13.6Hz, 1H, H8α), 2.66 (dd, J=2.8, 11.5 Hz, 1H, H2β), 4.45 (dd, J=5.5, 10.4Hz, 1H, H13β), 4.61 (d, J=5.0 Hz, 1H, H10β); ¹³C NMR δ (ppm) −5.4 (TBSCH₃), −4.6 (TBS CH₃), 4.3 (TES CH₂), 6.5 (TES CH₃), 14.1 (CH₃ 18), 17.9(TBS C(CH₃)₃), 19.1 (CH₃ 19), 25.4 (CH₃ 17), 25.8 (TBS C(CH₃)₃), 26.8(CH₃ 16), 33.5 (C14), 38.6 (C15), 39.4 (C2), 43.7 (C8), 44.4 (C9), 47.5(C1), 67.5 (C13), 69.5 (C10), 136.8 (C11), 138.8 (Cl2), 213.5 (C3); IR(CHCl₃) υ 2950, 2900, 1680, 1460, 1420, 1395, 1365, 1250, 1200, 1110,1080, 1000, 900, 860, 840 cm⁻¹; MS (CI) 481 (M+1, 3), 463 (16), 349(100), 331 (50); Anal. Calcd. for C₂₇H₅₂O₃Si₂: C, 67.44; H, 10.90.Found: C, 67.31; H, 10.78.

Ketocarbonate 6. To a stirred solution of diisopropylamine (0.60 mL,4.28 mmol) in THF (11 mL) under nitrogen at room temperature was added1.26 mL of a 3.1 M solution (3.89 mmol) of MeMgBr in ether. After 3 h, asolution of ketone 5 (P₁₀=TES, P₁₃=TBS) (750 mg, 1.56 mmol) in THF (3.5mL) was added dropwise at room temperature. After 1.5 h, the reactionmixture was cooled to −23° C. and a solution of 4-pentenal (327 mg, 3.89mmol) in THF (4 mL) was added dropwise down the side of the flask. After1 h, 10 mL of a saturated aqueous NH₄Cl solution was added. Ater 2 min,the reaction mixture was diluted with 100 mL of hexane, then poured into100 mL of H₂O. The organic phase was washed with 100 mL of H₂O and 100mL of brine, and dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give 0.92 g of a yellow oil. To a solution of thecrude mixture in CH₂Cl₂ (10 mnL) and pyridine (10 mL) under nitrogen at−23° C. was added 2.3 mL of 4 M solution (9.36 mmol) of phosgene intoluene dropwise and the reaction mixture was warmed to −10° C. After 30min, ethanol (3.7 mL) was added and the resulting mixture was stirredfor 30 min. The reaction mixture was then diluted with 300 mL of hexane,washed with 200 mL of a saturated aqueous NaHCO₃ solution, 200 mL of a10 % aqueous CuSO₄ solution, 200 mL of H₂O, 200 mL of a saturatedaqueous NaHCO₃ solution and 200 mL of brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to give 1.05 g of a yellowsolid. The crude mixture was filtered through silica gel with 10% ethylacetate in hexanes to give 965 mg of a white solid which was furtherpurified by silica gel chromatography eluting with 2% ethyl acetate inhexanes to yield 745 mg (75 %) of ketocarbonate 6 (P₁₀=TES, P₁₃=TBS,R=Et) as a white solid. The product was isolated as a 6:1 ratio ofconformational isomers. The following NMR data is for the predominantconformer.

6 (P₁₀=TES, P₁₃=TBS, R=Et): mp 103-104° C.; ¹H NMR (500 MHz, CDCl₃) δ0.08 (s, 3H, TBS CH₃), 0.08 (s, 3H, TBS CH₃), 0.56 (q, J=7.8 Hz, 6H, TESCH₂), 0.94 (t, J=7.8 Hz, 9H, TES CH₃), 0.96 (s, 9H, TBS t-Bu), 1.08 (s,3H, CH₃ 17), 1.29 (m, 1H, H6), 1.38 (s, 3H, CH₃ 19), 1.42 (s, 3H, CH₃16), 1.66 (dd, J=4.6, 12.5 Hz, 1H, H9α:), 1.83 (s, 3H, CH₃ 18), 1.85(dd, J=4.5, 4.5 Hz, 1H, H14α), 2.05 (m, 1H, H5), 2.06 (dd, J=6.4, 14.2Hz, 1H, H5), 2.47 (m, 2H, H9α, H6), 3.01 (dd, J=3.7, 12.3 Hz, 1H, H14β),4.20 (m, 2H, H2α, H2β), 4.47 (d, J=7.3 Hz, 1H, H13β), 4.50 (dd, J=4.6,11.4 Hz, 1H, H10β), 4.91 (dd, J=1.83, 10.1 Hz, 1H, H20), 4.97 (dd,J=1.8, 16.9 Hz, 1H, H20), 5.29 (dd, J=0.9, 10.1 Hz, 1H, H7), 5.73 (dddd,J=6.9, 6.9, 10.5, 16.9 Hz, 1H, H4); ¹³C NMR δ (ppm) −5.3 (TBS CH₃), −4.5(TBS CH₃), 4.8 (TES CH₂), 6.5 (TES CH₃), 14.0 (OEt CH₃), 15.5 (CH₃ 19),15.9 (CH₃ 18), 18.1 (TBS C(CH₃)₃), 25.8 (TBS C(CH₃)₃), 27.6 (CH₃ 17),28.2 (CH₃ 16), 30.4, 30.5 (C5, C6), 34.1 (C14), 39.0 (C15), 41.1 (C2),47.1 (C1), 47.5 (C9), 55.1 (C8), 63.8 (OEt CH2), 66.3 (C13), 68.3 (C10),84.0 (C7), 114.8 (C20), 134.8 (C11), 138.1 (C4′), 144.9 (C12), 155.7(Ethylcarbonate C═O), 214.8 (C3); IR (CCl₄) υ 3000, 2950, 2900, 1770,1700, 1490, 1390, 1280, 1140, 1100, 1030, 910, 880, 860 cm⁻¹; MS (EI)636 (M, 100), 593 (20), 538 (34), 409 (33); Anal. Calcd. forC₃₅H₆₄O₆Si₂: C, 65.99; H, 10.13. Found: C, 65.88, H, 10.17.

Hydroxyketone 7. To a stirred solution of ketocarbonate 6 (P₁₀=TES,P₁₃=TBS, R=Et) (4.00 g, 6.28 mmol) in THF (65 mL) under nitrogen at −35°C. was added 50 mL of a 0.2 M solution (10 mmol) of LDA in THF down theside of the flask over a 10 min period. After 30 min, the reactionmixture was cooled to −78° C. and 2.29 g of (R)-camphorylsulfonyloxaziridine (10 mmol) in THF (18 mL) was added dropwise down the side ofthe flask. After 30 min, the reacion mixture was quenched with 300 mL ofa saturated aqueous NaHCO₃ solution and extracted with 500 mL and then150 mL of 25% ethyl acetate in hexanes. The combined organic phases werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to yield 7 g of a waxy solid. This material waspurified by flash chromatography, eluting with 3% ethyl acetate inhexanes to yield 3.50 g of hydroxyketone 7 (P₁₀=TES, P₁₃=TBS, R=Et)(85%).

7 (P₁₀=TES, P₁₃=TBS, R=Et): ¹H NMR (500 MHz, CDCl₃) δ 0.01 (s, 3H, TBSCH₃), 0.03 (s, 3H, TBS CH₃), 0.50 (q, J=7.8 Hz, 6H, TES CH₂), 0.87 (t,J=7.8 Hz, 9H, TES CH₃), 0.90 (s, 9H, TBS t-Bu), 1.03 (s, 3H, CH₃ 17),1.25 (t, J=7.0 Hz, 3H, OEt CH₃), 1.35 (s, 3H, CH₃ 19), 1.40 (m, 1H, H6),1.41 (s, 3H, CH₃ 16), 1.66 (dd, J=4.6, 12.8 Hz, 1H, H9β), 1.77 (d, J=1.4Hz, 3H, CH₃ 18), 1.83 (dd, J=6.0, 14.7 Hz, 1H, H14α), 1.97 (dd, J =4.1,8.5 Hz, 1H, H1), 2.02 (m, 2H, H5, H5), 2.44 (dd, J=11.9, 11.9 Hz, 1H,H9α), 2.75 (d, J=10.5 Hz, 1H, OH—2), 4.14 (q, J=14.2 Hz, 2H, OEt CH₂),4.35 (dd, J=6.0, 8.7 Hz, 1H, H13), 4.42 (dd, J=4.6, 11.0 Hz, 1H, H10),4.49 (dd, J=4.1, 10.1 Hz, 1H, H2), 4.86 (dd, J=1.8, 10.3 Hz, 1H, H20),4.92 (dd, J=1.8, 16.9 Hz, 1H, H20), 5.23 (dd, J=1.4, 10.1 Hz, 1H, H7),5.67 (dddd, J=6.9, 6.9, 10.5, 16.9 Hz, 1H, H4); ¹³C NMR δ (ppm) −5.3(TBS CH₃), −4.5 (TBS CH₃), 4.7 (TES CH₂), 6.5 (TES CH₃), 14.0 (OEt CH₃),15.0 (CH₃ 19), 16.0 (CH₃ 18), 18.0 (TBS C(CH₃)₃), 25.8 (TBS C(CH₃)₃),27.5, 27.8 (CH₃ 17), 28.1 (CH₃ 16), 30.4, 30.5 (C5, C6), 36.9 (C15),47.3 (C9), 54.5 (C1), 54.7 (C8), 63.9 (OEt CH₂), 66.2 (C13), 67.8 (C10),70.3 (C2), 83.6 (C7), 114.9 (C20), 135.4(C11), 137.9 (C4′), 144.5 (C12),155.6 (Ethylcarbonate C═O), 217.8 (C3); IR (CCl₄) υ 3600, 2950, 2900,1750, 1700, 1660, 1470, 1400, 1370, 1240, 1080, 1050, 1000, 840, 680cm⁻¹; MS (CI) 653 (M+1, 8), 564 (100), 431 (69), 389 (67).

Hydroxycarbonate 8. To a vigorously stirred solution of hydroxyketone 7(P₁₀=TES, P₁₃=TBS, R=Et) (2.69 g, 4.12 mmol) in toluene (117 mL) undernitrogen at −78° C. was added dropwise down the side of the flask 85 mLof a 0.97 M solution (82.4 mmol) of RedAl in toluene. After 6 h at −78°C., the solution was allowed to gradually warm to room temperature overa period of 6 h. The mixture was recooled to −10° C. and 125 mL of a 2 Msolution (250 mmol) of acetic acid in THF was added dropwise down theside of the flask. The cloudy mixture was stirred 10 min then pouredinto 1200 mL of 50% ethyl acetate in hexanes and washed with 1 L of asaturated aqueous NaHCO₃ solution. The aqueous phase was extracted withfour 500 mL portions of ethyl acetate and the combined organic phaseswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to yield 2.29 g of 2,3,7-triol as a white solid.This material was used without further purification.

To a vigorously stirred solution of triol (2.29 g, 3.93 mmol) in CH₂Cl₂(157 mL) and pyridine (15.7 mL) under nitrogen at −78° C. was quicklyadded 7.6 mL of a 3.0 M solution (23 mmol) of phosgene in toluene. Thesolution was allowed to warm to room temperature over a period of 1 hthen poured into 250 mL of ethyl acetate, washed with two 125 mLportions of a saturated aqueous NaHCO₃ solution and 100 mL brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to yield2.52 g yellow oil. This material was filtered through a 2 inch pad ofsilica gel with 50% ethyl acetate in hexanes and concentration underreduced pressure yielded 2.39 g (95% from 7) of hydroxy carbonate 8(P₁₀=TES, P₁₃=TBS) as a white solid.

8 (P₁₀=TES, P₁₃=TBS): mp 155-157° C.; ¹H NMR (500 MHz, CDCl₃) δ 0.09 (s,3H, TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.59 (q, J=8.2 Hz, 6H, TES CH₂),0.96 (t, J=8.2 Hz, 9H, TES CH₃), 0.97 (s, 9H, TBS t-Bu), 1.11 (s, 3H,CH₃ 19), 1.14 (s, 3H, CH₃ 17), 1.30 (s, 3H, CH₃ 16), 1.39 (dd, J=4.1,13.3 Hz, 1H, H9β), 1.65 (m, 2H, H6, H6), 1.99 (dd, J=6.4, 15.1 Hz, 1H,H14α), 2.01 (d, J=0.9 Hz, 3H, CH₃ 18), 2.04 (d, J=3.7 Hz, 1H, H1), 2.11(ddd, J=7.8, 15.6, 15.6 Hz, 1H, H5), 2.28 (ddd, J=9.6, 9.6, 14.2 Hz, 1H,H14β), 2.34 (dd, J=12.4, 13.3 Hz, 1H, H9β), 2.41 (m, 1H, H5), 3.87 (dd,J=0.9, 10.5 Hz, 1H, H7), 3.95 (d, J=3.7 Hz, 1H, H2), 4.59 (dd, J=3.7,11.4 Hz, 1H, H10β), 4.40 (s, 1H, H3), 4.55 (dd, J=6.4, 8.7 Hz, 1H, H13),5.03 (d, J=10.5 Hz, 1H, H20), 5.07 (dd, J=1.5, 17.0 Hz, 1H, H20), 5.77(m, 1H, H4); ¹³C NMR δ (ppm) −5.4 (TBS CH₃), −4.4 (TBS CH₃), 4.8 (TESCH₂), 6.5 (TES CH₃), 15.5 (CH₃ 18), 17.9 (TBS C(CH₃)₃), 18.2 (CH₃ 19),25.6 (TBS C(CH₃)₃), 25.9 (CH₃ 16), 27.5 (CH₃ 17), 28.3 (C6), 28.4 (C5),29.8 (C14), 30.8 (C15), 36.5 (C8), 36.8 (C9), 37.3, 50.8 (C1), 66.6(C10), 67.8 (C13), 70.5 (C2), 91.9 (C3), 91.9 (C7), 116.3 (C20), 133.7(C11), 137.9 (C4′), 142.6 (C12), 148.0 (cyclic carbonate C═O); IR (CCl₄)υ 3450, 2950, 2870, 1750, 1460, 1380, 1350, 1220, 1120, 1080, 1040, 980,900, 820, 710 cm⁻¹; MS (CI) 625 (M+1—H₂O, 6), 551 (11), 477 (100), 459(12), 433 (8), 344 (90); Anal. Calcd. for C₃₃H₆₀O₆Si₂: C, 64.92; H,9.90; Found: C, 65.13; H, 9.88.

Ketocarbonate 9. To a vigorously stirred solution of dimethylsulfoxide(2.41 mL, 34 mmol) in CH₂Cl₂ (57 mL) under nitrogen at −78° C. was added8.5 mL of a 2.0 M solution (17.0 mmol) of oxalyl chloride in CH₂Cl₂.After 10 min, a solution of hyroxycarbonate 8 (P₁₀=TES, P₁₃=TBS) (3.45g, 5.67 mmol) in 16 mL CH₂Cl₂ was added dropwise down the side of theflask. After 30 min at −78 ° C., triethylamine (6.8 mL, 49 mmol) wasadded and the mixture was warmed to room temperature. The mixture wasdiluted with 200 mL hexanes, washed with two 75 mL portions of asaturated aqueous NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to yield 3.45 g of a yellowsolid. This material was filtered though a 1 inch pad of silica gel with10% ethyl acetate in hexanes and then recrystallized from hexanes toyield 2.62 g of ketocarbonate 9 as white crystals. The mother liquor waspurified by silica gel chromatography, eluting with 10% ethyl acetate inhexanes and then recrystallizaton from hexanes to yield an additional0.58 g of ketocarbonate 9 (P₁₀=TES, P₁₃=TBS) (total yield: 3.20 g, 93%).

9 (P₁₀=TES, P₁₃=TBS): mp 140.0-141.5° C.; ¹H NMR (500 MHz, CDCl₃) δ 0.11(s, 3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.60 (q, J=7.8 Hz, 6H, TESCH₂), 0.96 (t, J=7.8 Hz, 9H, TES CH₃), 0.98 (s, 9H, TBS t-Bu), 1.06 (s,3H, CH₃ 19), 1.17 (s, 6H, CH₃ 16, CH₃ 19), 1.42 (dd, J=3.7, 14.2 Hz, 1H,H9β), 1.63 (m, 2H, H6, H6), 2.12 (m, 1H, H5), 2.38 (d, J=0.9 Hz, 3H, CH₃18), 2.47 (dd, J=11.4, 13.3 Hz, 1H, H9α), 2.65 (d, J=8.2, 1H, H1), 3.94(dd, J=1.4, 10.4 Hz, 1H, H7), 4.44 (dd, J=3.7, 11.4 Hz, 1H, H10), 4.49(s, 1H, H3), 4.64 (dd, J=6.9, 7.8 Hz, 1H, H13), 5.04 (dd, J=1.4, 11.9Hz, 1H, H20), 5.07 (dd, J=1.8, 17.4 Hz, 1H, H20), 5.76 (m, 1H, H4); ¹³CNMR δ (ppm) −5.4 (TBS CH₃), −4.5 (TBS CH₃), 4.8 (TES CH₂), 6.5 (TESCH₃), 15.7 (CH₃ 18), 17.8 (CH₃ 19), 17.9 (TBS C(CH₃)₃), 25.5 (TBSC(CH₃)₃), 28.2 (CH₃ 16), 28.3 (CH₃ 17), 28.3 (C6), 29.6 (C5), 30.4(C14), 37.7 (C15), 38.0 (C8, C9), 62.1 (C1), 66.5 (C10), 67.5 (C13),91.3 (C3), 91.5 (C7), 116.4 (C20), 132.8 (C11), 137.0 (C4′), 145.4(C12), 146.6 (cyclic carbonate C═O), 206.8 (C2); IR (CCl₄) υ 2930, 2860,1760, 1670, 1450, 1380, 1340, 1240, 1180, 1170, 1120, 1090, 1060, 1040,980, 890, 860, 820, 700, 650 cm⁻¹; MS (CI) 607 (M+1, 6), 549 (11), 475(100), 431 (4), 347 (45); Anal. Calcd. for C₃₃H₅O₆Si₂: C, 65.30; H,9.63; Found: C, 65.23; H, 9.66.

2-Keto-3-Hydroxy-Lactone 10. To a stirred solution of 3,7-cycliccarbonate 9 (P₁₀=TES, P₁₃ =TBS) (2.246 g, 3.70 mmol) in THF (9 mL) wasadded 19.4 mL of 0.2 M LTMP (3.88 mmol) in THF dropwise down the sidesof the flask at −25° C. The reaction mixture was allowed to warm to −10°C. over the course of 30 min. The cold reaction mixture was poured into100 mL of 10% aqueous acetic acid and extracted with 100 mL of 10 %ethyl acetate in hexanes. The organic phase was washed with 50 mL of asaturated aqueoues NaHCO₃ solution and 50 mL of brine. The combinedaqueous phases were extracted with two 20 mL portions of 10% ethylacetate in hexanes. The oraganic phases were combined, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 2.4 gof a yellow oil. This material was purified by silica gelchromatography, eluting with 5% then 10% ethyl acetate in hexanes toyield 2.033 g (90%) of the hydroxy lactone 10 (P₁₀=TES, P₁₃=TBS) as afoamy solid and 0.207 g (7.2%) of the 3-carbamate.

10 (P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃) δ 0.12 (s, 3H, TBS CH₃),0.14 (s, 3H, TBS CH₃), 0.61 (q, J=7.8 Hz, 6H, TES CH₂), 0.92 (s, 9H, TBSt-Bu), 0.97 (t, J=7.8 Hz, 9H, TES CH₃), 1.11 (s, 3H, CH₃ 17), 1.22 (s,3H, CH₃ 19), 1.27 (s, 3H, CH₃ 16), 1.32 (dd, J=3.2, 13.3 Hz, 1H, H9β),1.64 (ddd, J=2.3, 6.9, 9.2 Hz, 1H, H6), 2.07 (m, 2H, H6, H5), 2.17 (m,1H, H14α), 2.33 (m, 1H, H5), 2.65 (m, 2H, H14β, H1), 2.74 (dd, J=12.4,12.4 Hz, 1H, H9α), 3.92 (dd, J=2.8, 11.5 Hz, 1H, H7), 4.47 (dd, J=3.2,11.0 Hz, 1H, H10), 4.55 (dd, J=2.8, 9.6 Hz, 1H, H13), 5.02 (d, J=10.1Hz, 1H, H20), 5.07 (dd, J=1.4, 16.9 Hz, 1H, H20), 5.81 (dddd, J=6.9,6.9, 10.5, 16.9 Hz, 1H, H4); ¹³C NMR δ (ppm) −5.2 (TBS CH₃), −4.5 (TBSCH₃), 4.8 (TES CH₂), 6.6 (TES CH₃), 16.4 (CH₃ 18), 17.9 (TBS C(CH₃)₃),24.2 (CH₃ 19), 25.7 (TBS C(CH₃)₃), 26.9 (CH₃ 16), 30.1 (CH₃ 17), 30.4(C5), 32.7 (C6), 32.9 (C14), 39.1 (C15), 40.6 (C9), 48.1 (C8), 62.0(C1), 67.3 (C10), 67.6 (C13), 87.9 (C3), 91.1 (C7), 115.8 (C20), 137.7(C11), 138.5 (C4′), 143.0 (C12), 173.5 (C4), 207.6 (C2); IR (CCl₄) υ3500, 2970, 2900, 1780, 1700, 1480, 1360, 1260, 1210, 1160, 1070, 1010,910, 890, 840 cm⁻¹; MS (EI) 606 (M, 100), 549 (69), 474 (27), 431 (65),417(40); Anal. Calcd. for C₃₃H₅₈O₆Si₂: C, 65.30; H, 9.63; Found: C,65.38; H, 9.64.

Keto Lactone 11. To the 2-keto-3-hydroxylactone 10 (P₁₀=TES, P₁₃=TBS)(1.10 g, 1.83 mmol) was added a 0.1 M solution of SmI₂ in THF (82 mL,8.2 mmol). The resulting dark blue solution was stirred at roomtemperature under N₂ for 4 h. After cooling to 0° C. an etherealsolution of HCl (0.66M; 4.2 mL, 2.77 mmol) was added; after 5 min theflask was opened to the air and the reaction mixture was diluted with200 mL of cold ethyl acetate, then poured into 50 mL of ice cold 0.2Naqueous HCl. The organic phase was separated and washed with 50 mL of a5% aqueous citric acid solution, two 50 mL portions of a saturatedaqueous NaHCO₃ solution and 50 mL of brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The resulting material wasdissolved in 100 mL of hexanes, then silica gel (230-400 mesh; 4.3 g)was added and the mixture was vigorously stirred at room temperature for65 min before filtering through a 1 inch pad of silica gel eluting with300 mL of 20% ethyl acetate in hexanes. The solvent was evaporated underreduced pressure and the residue was purified by silica gelchromatography, eluting with 10% ethyl acetate in hexanes to yield 822mg (77%) of the cis-ketolactone 11 and 164 mg (15%) of the correspondingtrans isomer.

To a solution of the trans-2-ketolactone (611 mg, 1.03 mmol) stirred in10 mL of THF under nitrogen at 0° C. was added down the side of theflask 6.8 mL of a 0.6 M solution (4.1 mmol) of t-BuOK in THF. Theresulting solution was stirred for 1.5 h then 10 mL of a 10% acetic acidsolution in THF was added down the side of the flask. After stirring for5 min the mixture was diluted with 200 mL of hexanes and poured into 100mL of a saturated aqueous NaHCO₃ solution. The organic layer was washedwith water and brine then dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to yield 615 mg of pale brown oil. The oil wasdissolved in 10 mL of hexanes and silica gel (3.0 g) was added. Themixture was stirred vigorously for 15 min then filtered through a ½ inplug of silica gel with 20% ethyl acetate in hexanes. Concentration ofthe filtrate under reduced pressure yielded 576 mg of pale yellow oil.This material was purified by silica gel chromatography, eluting with10% then 20% ethyl acetate in hexanes to yield 472 mg (77%) of purecis-2-ketolactone 11 (P₁₀=TES, P₁₃=TBS), 84 mg (13%) of pure transisomer and 24 mg of a 6:1 mixture of cis:trans isomers.

11 (P₁₀=TES, P₁₃=TBS): mp=86.5-88.0° C.; ¹H NMR (500 MHz, CDCl₃) δ 0.05(s, 3H, TBS CH₃), 0.07 (s, 3H, TBS CH₃), 0.54 (q, J=7.8 Hz, 6H, TESCH₂), 0.84 (s, 9H, TBS t-Bu), 0.90 (t, J=7.8 Hz, 9H, TES CH₃), 1.03 (s,3H, CH₃ 17), 1.11 (s, 3H, CH₃ 16), 1.15 (s, 3H, CH₃ 19), 1.35 (dddd,J=4.6, 4.6, 7.3, 14.2 Hz, 1H, H6), 1.43 (dd, J=3.7, 12.8 Hz, 1H, H9β),1.67 (dddd, J=3.2, 7.3, 10.1, 13.7 Hz, 1H, H6), 1.83 (dd, J=4.6, 16.0Hz, 1H, H14α), 2.03 (m, 1H, H5), 2.07 (d, J=1.4 Hz, 3H, CH₃ 18), 2.25(m, 1H, H5), 2.30 (dd, J=11.9, 12.3 Hz, 1H, H9α), 2.45 (d, J=8.2 Hz, 1H,H1), 2.58 (ddd, J=8.7, 9.2, 16.0 Hz, 1H, H14β), 3.93 (dd, J=2.8, 11.4Hz, 1H H7β), 4.03 (s, 1H, H3α), 4.37 (dd, J=3.7, 11.0 Hz, 1H, H10β),4.46 (ddd, J=1.4, 4.6, 9.2 Hz, 1H, H13β), 4.96 (dd, J=1.4, 10.1 Hz, 1H,H20), 5.01 (dd, J=1.4, 17.4 Hz, 1H, H20), 5.73 (dddd, J=6.4, 7.3, 10.5,16.9 Hz, 1H, H4); ¹³C NMR δ (ppm) −5.3 (TBS CH₃), −4.6 (TBS CH₃), 4.5(TES CH₂), 6.5 (TES CH₃), 15.0 (CH₃ 18), 18.0 (TBS C(CH₃)₃), 25.7 (TBSC(CH₃)₃), 28.9 (CH₃ 19), 29.2 (CH₃ 16), 29.8 (C5), 29.9 (CH₃ 17), 30.3(C6), 32.8 (C14), 38.5 (C15), 44.2 (C8), 44.9 (C9), 60.6 (C3), 61.2(C1), 66.9 (C10), 67.8 (C13), 91.9 (C7), 115.7 (C20), 137.7 (C 11),138.5 (C4′), 142.4 (C12), 174.7 (C4), 204.8 (C2); IR (CCl₄) υ 2975,2899, 1780, 1705, 1460, 1355, 1260, 1180, 1070, 1060, 1000, 830 cm⁻¹; MS(CI) 591 (M+1, 5), 523 (6), 459(100), 441 (5); Anal. Calcd. forC₃₃H₅₈O₅Si₂: C, 66.07; H, 9.89; Found: C, 66.97; H, 9.91.

1-Hydroxy-2-Keto-Lactone 12. To 34.2 mL of a stirred 0.2 M solution(6.84 mmol) of LTMPi in THF under nitrogen at −10° C. was added asolution of ketolactone 11 (P₁₀=TES, P₁₃=TBS) (1.008 g, 1.71 mmol) in 10mL of THF dropwise down the side of the flask. After 0.5 h, the reactionmixture was cooled to −40° C. and a solution of (±)-camphorsulfonyloxaziridine (1.96 g, 8.55 mmol) in THF (10 mL) was added dropwise downthe side of the flask. After 20 min, the reaction mixture was cooled to−78° C., diluted with 200 mL of hexanes and rapidly poured into 250 mLof a vigorously stirred saturated aqueous NH₄Cl solution. The aqueousphase was extracted with two 50 mL portions of hexane and the combinedorganic phase were dried over anhydrous Na₂SO₄ and concetrated underreduced pressure to give 1.4 g of a waxy solid. This material waschromatographed (CH₂Cl₂ followed by hexanes increasing to 10% ethylacetate in hexanes) to give 0.882 g of hydroxyketolactone 12 (P₁₀=TES,P₁₃=TBS) (85%) as a white solid, 0.083 g of the correspondingtrans-hydroxyketolactone (8%) as a solid, and 31 mg of returnedketolactone 11 (3%).

12 (P₁₀=TES, P₁₃=TBS): mp 124-126° C.; 1H NMR (C₆D₆) δ (ppm) 0.09 (s,3H, CH₃ in TBDMS), 0.17 (s, 3H, CH₃ in TBDMS), 0.62 (q, J=7.78 Hz, 6HCH₂'s in TES), 1.03 (t, J =7.78, 9H CH₃'s in TES), 1.05 (s, 3H, CH₃19),1.13 (s, 9H, t-Bu in TBS), 1.20 (s, 3H, CH₃17), 1.39 (m, 1H, H6), 1.42(s, 3H, CH₃16), 1.44 (dd, J=0.92, 13.28 Hz, 1H, H9β), 1.98 (dd, J=9.61,12.82 Hz, 1H, H14β), 2.05 (m, 1H, H5), 2.06 (broad, 1H, OH1, D₂Oexchangable), 2.25 (m, 1H, H6), 2.27 (d, J=0.91 Hz, 3H, CH₃18), 2.29 (m,1H, H5), 2.41 (dd, J=10.98, 13.28 Hz, 1H, H9α), 2.56 (dd, J=3.21, 12.82Hz, 1H, H14α), 3.83 (dd, J=2.75, 11.90 Hz, 1H, H7), 4.04 (s, 1H, H3),4.47 (dd, J=0.92, 10.98 Hz, 1H, H10), 4.60 (ddq, J=0.91, 3.21, 9.61 Hz,1H, H13), 5.11 (br d, J=10.53 Hz, 1H, H20), 5.18 (br d, J=17.40 Hz, 1H,H20), 5.77 (m, 1H, H4); 13C NMR (CDCl₃) δ (ppm) −5.4 (TBS CH₃), −4.7(TBS CH₃), 4.5 (TES CH₂), 6.5 (TES CH₃), 15.5 (CH₃ 18), 17.9 (TBSC(CH₃)₃), 22.5 (CH₃ 19), 25.7 (TBS C(CH₃)₃), 26.3 (CH₃ 16), 29.8 (CH₃17), 29.8 (C5), 30.4 (C6), 39.6 (C14), 41.3 (C15), 44.5 (C9), 45.0 (C8),58.1 (C3), 66.5 (C10), 68.2 (C13), 83.0 (C1), 91.7 (C7), 115.7 (C20),137.0 (C11), 137.6 (C4′), 145.5 (C12), 175.0 (C4), 202.4 (C2); IR (CCl₄)υ 3500, 3000, 1780, 1720, 1100 cm⁻¹; MS (CI) 607 (M+1, 10), 589 (56),475 (100), 457 (61); Anal. Calcd for C₃₃H₅₈O₆Si₂: C, 65.30; H, 9.63.Found: C, 65.19; H, 9.60.

1,2-Dihydroxy-trans-lactone 13. To a stirred 1.23 M solution of Red-Al(4.6 mmol, 5.6 mmol) in THF under nitrogen at −78° C. was quickly addeda solution of cis-hydroxyketone 12 (P₁₀=TES, P₁₃=TBS) (342 mg, 0.563mmol) in THF (25 mL). After 1.5 h, 25 mL of a 15% aqueous NaOH solutionwas added dropwise directly to the reaction mixture. The reactionmixture was vigorously stirred at room temperature for 3 h and was thenpoured into 100 mL of H₂O and extracted with two 100 mL portions ofether. The organic phases were combined and washed with 100 mL of H₂Oand 100 mL of brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give 0.35 g of a pale yellow solid. This materialwas purified by silica gel chromatography eluting with 10% ether inhexanes followed by 25% ethyl acetate in hexanes to yield 290 mgtrans-diol 13 as colorless needles, 14.5 mg (4.2%) oftrans-hydroxyketone, and 20 mg of a mixture of cis-diol and unknownbyproducts. To a solution of the mixture containing cis-diol diol in ThF(1 mL) under nitrogen at room temperature was added 0.5 mL a 30% aqueoussolution of NaOH. After 2.5 h, the reaction mixture was poured into 30mL of H₂O and extracted with 30 mL of ether. The organic phase waswashed with 30 mL of H₂O and 30 mL of brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to give 0.02 g of a yellowsolid, which was purified by silica gel chromatography eluting with 5%ethyl acetate in hexanes to yield an additional 12 mg (total yield: 302mg, 88%) of trans-diol 13 (P₁₀=TES, P₁₃=TBS). 13 (P₁₀=TES, P₁₃=TBS): mp127-128° C., ¹H NMR (500 MHz, CDCl₃) δ 0.09 (s, 3H, TBS CH₃), 0.11 (s,3H, TBS CH₃), 0.60 (q, J=8.1 Hz, 6H, TES CH₂), 0.87 (s, 9H, TBS t-Bu),0.96 (t, J=8.1 Hz, 9H, TES CH₃) 1.13 (s, 3H, CH₃ 17), 1.23 (s, 3H, CH₃16), 1.31 (s, 3H, CH₃ 19), 1.42 (dd, J=3.7, 12.8 Hz, 1H, H9β), 1.46(ddd, J=4.8, 8.8, 11.4 Hz, 1H, H6), 1.74 (dddd, J=3.3, 7.3, 9.9, 12.4Hz, 1H, H6), 1.99 (d, J=1.5 Hz, 3H, CH₃ 18), 2.10 (m, 1H, H5), 2.21 (dd,J=3.7, 5.4 Hz, 1H, H14α), 2.26 (m, 3H, H5, H9α, H14β), 2.92 (d, J=7.7Hz, 1H, H3), 3.84 (dd, J=2.2, 7.7 Hz, 1H, H2), 3.85 (s, 1H, OH1), 3.97(dd, J=2.9, 11.4 Hz, 1H, H7), 4.47 (dd, J=3.7, 11.4 Hz, 2H, H13, H10),5.01 (dd, J=1.8, 12.2 Hz, 1H, H20), 5.07 (dd, J=1.7, 17.0 Hz, 1H, H20),5.78 (dddd, J=7.3, 7.3, 10.1, 16.5 Hz, 1H, H4), 6.87 (d, J=2.9 Hz, 1H,OH2), ¹³C NMR (CDCl₃) δ (ppm) −5.31, −4.59, 4.79, 6.55, 16.60, 17.68,21.24, 24.70, 25.62, 28.50, 29.52, 30.05, 40.20, 40.41, 44.18, 45.18,45.60, 66.62, 69.25, 71.32, 88.91, 116.09, 136.96, 138.63, 139.93,180.10, IR (CHCl₃) υ 3050, 1730, 1460, 1350 cm⁻¹, MS (EI) 608 (M, 13),590 (26), 267 (100), Anal. Calcd. for C₃₃H₆₀O₆Si₂: C, 65.08; H, 9.92.Found C, 65.06; H, 9.98.

Carbonate 14. To a stirred solution of diol 13 (P₁₀=TES, P₁₃=TBS) (1.00g, 1.64 mmol) in CH₂Cl₂ (58 mL) and pyridine (5.8 mL) under nitrogen at−78° C. was added dropwise 8.2 mL of 2 M solution (16.4 mmol) ofphosgene in toluene. Then the reaction mixure was warmed to −23° C. andstirred for 30 min. To the resulting mixture, 50 mL of a saturatedaqueous NaHCO₃ solution was added. After warming to room temperature for10 min, the reaction mixture was extracted with 200 mL of 10% ethylacetate in hexanes. The organic phase was washed with 100 mL of a 10%aqueous CuSO₄ solution, two 200 mL portions of a saturated aqueousNaHCO₃ solution and brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to give 1.1 g of a pale yellow solid. Thismaterial was filtered through a 3 inch pad of silica gel with 15% ethylacetate in hexanes to yield 1.045 g (100%) of carbonate 14 (P₁₀=TES,P₁₃=TBS) as a white solid.

14 (P₁₀=TES, P₁₃=TBS): mp 146-147° C., ¹H NMR (500 MHz, CDCl₃) δ 0.11(s, 3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.61 (q, J=7.8 Hz, 6H, TESCH₂), 0.88 (s, 9H, TBS t-Bu), 0.96 (t, J=7.8 Hz, 9H TES CH₃), 1.20 (s,3H, CH₃ 17), 1.30 (s, 3H, CH₃ 16), 1.32 (s, 3H, CH₃ 19), 1.40 (ddd,J=2.7, 4.5, 9.2 Hz, 1H, H6), 1.44 (d, J=3.7, 13.3 Hz, 1H, H9β), 1.71(dddd, J=2.7, 6.9, 9.6, 12.8 Hz, 1H, H6), 2.11 (ddd, J=7.8, 15.3, 15.3Hz, 1H, H5), 2.29 (dd, J=3.2, 15.6 Hz, 1H, H14α), 2.31 (m, 2H, H5, H9α),2.59 (dd, J=9.2, 15.6 Hz, 1H, H14β), 2.99 (d, J=7.3 Hz, 1H, H3α), 4.02(dd, J=2.7, 11.4 Hz, 1H, H7 β), 4.38 (dd, J=3.7, 11.0 Hz, 1H, H10β),4.47 (d, J=7.3 Hz, 1H, H20β), 4.57 (dd, J=2.1, 9.2 Hz, 1H, H13β), 5.02(dd, J=1.4, 10.1 Hz, 1H, H20), 5.06 (dd, J=1.4, 16.9 Hz, 1H, H20), 5.77(dddd, J=6.9, 6.9, 10.1, 17.0 Hz, 1H, H4), ¹³C NMR (CDCl₃) δ (ppm)−5.37, −4.60, 4.75, 6.51, 17.02, 17.60, 21.24, 24.64, 25.55, 27.36,29.50, 30.11, 37.56, 39.96, 42.89, 43.75, 45.39, 66.54, 68.29, 87.37,90.05, 116.15, 136.54, 136.94, 144.93, 153.32, 169.89, IR (CHCl₃) υ3070, 1800 cm⁻¹, MS (EI) 634 (M, 12), 577 (100), Anal. Calcd. forC₃₄H₅₈O₇Si₂: C, 64.31; H, 9.21. Found C, 64.41; H, 9.22.

Ketoester 15. To a stirred solution of lactone 14 (P₁₀=TES, P₁₃=TBS)(1.05g, 1.65 mmol) in methanol (70 mL) under nitrogen at −78° C. wasadded a saturated solution of ozone in methylene chloride (50 mL, 40 mLthen 8 mL) until no more starting material remained by TLC analysis.Triethylamine (4.8 mL) and trimethylphosphite (3.1 mL) were addedsequentially to the resulting mixture at −78° C. After stirring 5 min,the solution was warmed to 0° C. and stirred for 2 h. The resultingsolution was poured into 250 mL of a saturated aqueous NaHCO₃ solutionand extacted with three 200 mL portions of CH₂Cl₂. The combined organiclayers were washed with 150 mL of a saturated NaHCO₃ solution, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to give1.10 g of the aldehyde as a colorless oil. This material was usedfurther purification.

To a stirred solution of the aldehyde (1.10 g) in t-butanol (30.8 mL),acetone (10.3 mL) and 8 mL of a 1.25 M (10 mmol) aqueous KH₂PO₄ solutionat 0° C. was added 11.3 mL of a 1 M (11.3 mmol) aqueous KMnO₄ solutionover the course of 2 min. The reaction mixture was stirred at 0° C. for30 min, poured into 200 mL of a 10% aqueous Na₂S₂O₃ solution andextracted with three 200 mL portions of ethyl acetate. The combinedorganic layers were washed with 50 mL of water, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. To a stirred solution ofthe oily residue in ether (30 mL) at room temperature was added anethereal solution of CH₂N₂ (20 mL). The solution was concentrated underreduced pressure to give 1.15 g of a colorless oil. This material wasfiltered through a 2 inch pad of silica gel with 40% ethyl acetate inhexanes and concentration under reduced pressure yielded 1.01 g (91%) oflactone ester 15 (P₁₀=TES, P₁₃=TBS, R=Me).

15 (P₁₀=TES, P₁₃=TBS, R=Me): ¹H NMR (500 MHz, CDCl₃) δ 0.12 (s, 3H, TBSCH₃), 0.12 (s, 3H, TBS CH₃), 0.60 (q, J=8.1 Hz, 6H, TES CH₂), 0.88 (s,9H, TBS t-Bu), 0.96 (t, J=8.1 Hz, 9H, TES CH₃), 1.21 (s, 3H, CH₃), 1.30(s, 3H, CH₃), 1.33 (s, 3H, CH₃), 1.51 (dd, J=3.7, 13.2 Hz, 1H, H9β),1.53 (m, 1H, H6), 2.06 (d, J=1.1 Hz, 3H, CH₃ 18), 2.07 (ddd, J=2.9, 7.7,21.6 Hz, 1H, H6), 2.29 (dd, J=3.7, 15.8 Hz, 1H, H14α), 2.31 (dd, J=13.2,13.2 Hz, 1H, H9α), 2.46 (ddd, J=7.7, 16.8, 24.5 Hz, 1H, H5), 2.53 (ddd,J=5.5, 7.7, 16.8 Hz, 1H, H5), 2.60 (dd, J=9.2, 15.8 Hz, 1H, H14β), 2.99(d, J=7.3 Hz, 1H, H3α), 3.68 (s, 3H, CO₂Me), 4.09 (dd, J=2.6, 12.1 Hz,1H, H7β), 4.39 (dd,J=3.7, 11.0 Hz, 1H, H10β), 4.47 (d, J=7.3 Hz, 1H,H2β), 4.59 (dd, J=1.8, 9.2 Hz, 1H, H13β); Anal. Calcd. for C₃₄H₅₈O₉Si₂:C, 61.22; H, 8.77. Found C, 61.30; H, 8.79.

Enol ester 16. To a stirred solution of lactone ester 15 (P₁₀=TES,P₁₃=TBS, R=Me) (1.01 g, 1.51 mmol) in THF (24.5 mL) at −78° C. was addedslowly a 19.4 mL of a 0.2 M solution (3.88 mmol) of LDA in THF down theside of the flask over the course of 3 min. After stirring 35 min, 10 mLof a 33% solution of acetic acid in THF was quickly added. After 5 min,the mixture was poured into 150 mL of a saturated aqueous NaHCO₃solution and extracted with three 200 mL portions of CHCl₃. The combinedorganic phases were dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give 1.02 g of crude enol ester 16 (P₁₀=TES,P₁₃=TBS, R=Me) as a colorless oil. Approximately 3% of unreacted esterlactone 15 was still present but this rnaterial was used without furtherpurification.

16 (P₁₀=TES, P₁₃=TBS, R=Me): ¹H NMR (300 MHz, CDCl₃) δ 0.09 (s, 3H, TBSCH₃), 0.10 (s, 3H, TBS CH₃), 0.61 (q, 6H, TES CH₂), 0.87 (s, 9H, TBSt-Bu), 0.96 (t, J=8.0 Hz, TES CH₃), 1.08 (s, 3H, CH₃), 1.21 (s, 3H,CH₃), 1.33 (S, 3H, CH₃), 1.61 (d, J=4.3 Hz, 1H, OH-7), 1.89 (dd, J=4.3,13.9 Hz, 1H, H9α), 1.95 (dd, J=11.2, 11.2 Hz, 1H, H9β), 2.01 (d, J=1.1Hz, 3H, CH₃ 18), 2.22 (ddd, J=2.7, 10.7, 15.5 Hz, 1H, H6β), 2.45 (dd,J=4.8, 15.5 Hz, 1H, H6α), 2.54 (dd, J=9.1, 15.0 Hz, 1H, H14β), 2.86 (dd,J=3.7, 15.0 Hz, 1H, H14α), 3.07 (s, 1H, H3α), 3.40 (ddd, J=4.8, 4.8, 9.6Hz, 1H, H7α), 3.75 (s, 3H, CO₂Me ), 4.39 (dd,J=4.3, 11.2 Hz, 1H, H10β),4.60 (d, J=4.3, 11.2 Hz, 1H, H2β), 4.67 (dd, J=2.1, 9.1 Hz, 1H, H13β),12.24 (s, 1H, OH4).

Enol ester 17. To a stirred solution of crude enol ester 16 (P₁₀=TES,P₁₃=TBS, R=Me) (1.02 g) in THF (13 mL) and 2-methoxypropene (13 mL)under nitrogen at 0° C. was added 0.48 mL of a 0.1 M solution (0.048mmol) of p-toluenesulfonic acid in THF. The mixture was stirred at 0° C.for 10 min and then triethylamine (0.66 mL) was added. The mixture wasconcentrated under reduced pressure and purified by silica gelchromatography, eluting with 7.5% ethyl acetate in hexanes increasing to30% ethyl acetate in hexanes to yield 938 mg enol ester 17 (P₇=MOP, P₁₀=TES, P₁₃=TBS, R=Me) (84% from 15) and 30 mg (3%) of recovered lactoneester 15.

17 (P₇=MOP, P₁₀=TES, P₁₃=TBS, R=Me): mp 95-97° C., ¹H NMR (300 MHz,CDCl₃) δ 0.08 (s, 3H, TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.59 (q, J=7.7Hz, 6H, TES CH₃), 0.87 (s, 9H, TBS t-Bu), 0.95 (t, J=7.7 Hz, 9H, TESCH₃), 1.10 (s, 3H, CH₃), 1.19 (s, 3H, CH₃), 1.30 (s, 3H, CH₃), 1.34 (s,3H, MOP CH₃), 1.37 (s, 3H, MOP CH₃), 1.84 (m, 2H, H9α, H9β), 1.98 (s,3H, CH₃ 18), 2.17 (ddd, J=2.8, 10.4, 15.9 Hz, 1H, H6β), 2.52, (dd,J=9.3, 15.4 Hz, 1H, H14β), 2.63 (dd, J=4.4, 15.9 Hz, 1H, H6α), 2.88 (dd,J=3.8, 15.4 Hz, 1H, H14α), 3.06 (s, 1H, H3α), 3.26 (s, 3H, MOP OMe),3.37 (dd, J=4.4, 10.4 Hz, 1H, H7α), 3.72 (s, 3H, CO₂Me), 4.36 (dd,J=6.0, 9.3 Hz, 1H, H10β), 4.57 (d, J=2.2 Hz, 1H, H2β), 4.67 (dd, J=2.8,9.3 Hz, 1H, H13β), 12.24 (s, 1H, OH4).

Enol ester 17 (P₇=TES). To a solution of the enol ester 16 (P₁₀=TES,P₁₃=TBS, R=Me) (9 mg, 0.0137 mmole) and DMAP (3.5 mg, 0.0286 mmole) inpyridine (0.6 mL) at 0° C. was added triethylsilyl chloride (0.025 mL,0.14 mmole). The solution was stirred at room temperature for 16 h,diluted with ethyl acetate (10 mL), poured into a saturated aqueoussodium bicarbonate solution (20 mL) and extracted with 20% ethylacetate/hexane (20 mL×3). The combined organic layer was dried overanhydrous NaSO₄, filtered and concentrated to yield 25 mg of crude 17.Column chromatography (10% ethyl acetate/hexane) provided 10 mg (95%) ofpure enol ester 17 (P₇=P₁₀=TES, P₁₃=TBS, R=Me).

17 (P₇=P₁₀=TES, P₁₃=TBS, R=Me): ¹H NMR (300 MHz, CDCl₃) δ 0.08 (s, 3H,TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.59 (q, J=8.1 Hz, 12H, TES CH₂), 0.87(s, 9H, TBS t-Bu), 0.95 (t, J=7.7 Hz, 18H, TES CH₃), 1.05 (s, 3H, CH₃),1.19 (s, 3H, CH₃), 1.30 (s, 3H, CH₃), 1.84 (m, 2H, H9α, H9β), 1.98 (s,3H, CH₃ 18), 2.17 (ddd, J=2.8, 10.4, 15.9 Hz, 1H, H6β), 2.31 (dd, J=4.4,15.9 Hz, 1H, H6α), 2.52, (dd, J=9.3, 15.4 Hz, 1H, H14β), 2.85 (dd,J=3.8, 15.4 Hz, 1H, H14α), 3.03 (br s, 1H, H3α), 3.34 (dd, J=5.0, 10.4Hz, 1H, H7α), 3.75 (s, 3H, CO₂Me OMe), 4.36 (dd, J=5.0, 10.4 Hz, 1H,H100β), 4.58 (d, J=2.7 Hz, 1H, H2β), 4.66 (br d, J=11.0 Hz, 1H, H13β),12.22 (s, 1H, OH4).

Ketone 18. To a stirred solution of enol ester 17 (P₇=MOP, P₁₀=TES,P₁₃=TBS, R=Me) (963 mg, 1.3 mmol) in DMF (30 mL) under nitrogen at roomtemperature was added solid potassium thiophenoxide (250 mg, 1.69 mmol)followed by thiophenol (0.4 mL, 3.9 mmol). The solution was warmed to86° C. for 3.5 hours. The solution was allowed to cool to roomtemperature then was poured directly into 250 mL of a saturated aqueousNaHCO₃ solution and extracted with three 150 mL portions of 30% ethylacetate in hexanes. The combined organic phases were then filteredthrough a 2 inch silica gel pad and subsequently concentrated underreduced pressure to yield 1.29 g of crude product. This material waspurified by radial chromatography, eluting with 15% then 20% and finally25% ethyl acetate in hexanes to yield 763 mg (86%) of ketone 18 (P₇=MOP,P₁₀=TES, P₁₃=TBS).

18 (P₇=MOP, P₁₀=TES, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.10 (s, 3H,TBS CH₃), 0.14 (s, 3H, TBS CH₃), 0.58 (q, J=8.2 Hz, 6H, TES CH₂), 0.94(s, 9H, TBS t-Bu), 0.95 (t, J=8.2 Hz, 9H, TES CH₃), 1.22 (s, 3H, CH₃19), 1.30 (s, 3H, CH₃ 17), 1.32 (s, 6H, MOP CH³), 1.33 (s, 3H, CH₃ 16),1.80 (m, 1H, H5), 1.81 (dd, J=3.8, 3.8 Hz, 1H, H9β), 1.98 (m, 1H, H5),1.99 (d, J=1.1 Hz, 3H, CH₃ 18), 2.21 (m, 1H, H6β), 2.29 (dd, J=10.4,12.1 Hz, 1H, H9α), 2.43 (dd, J=9.3, 15.4 Hz, 1H, H14α), 2.53 (m, 1H,H6α), 2.63 (dd, J =5.0, 15.4 Hz, 1H, H14β), 2.70 (d, J=5.0 Hz, 1H, H3),3.20 (s, 3H, MOP OMe), 3.39 (dd, J=6.1, 10.4 Hz, 1H, H7), 4.34 (dd,J=3.9, 10.4 Hz, 1H, H10), 4.55 (d, J=5.5 Hz, 1H, H2), 4.73 (dd, J=5.3,7.7 Hz, 1H, H13). Anal. Calcd. for C₃₆H₆₄O₈Si₂: C, 63.49; H, 9.47. FoundC, 63.56; H, 9.55. 18 (P₇=P₁₀=TES, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ0.10 (s, 3H, TBS CH₃), 0.14 (s, 3H, TBS CH₃), 0.47-0.63 (m, 12H, TESCH₂), 0.90-0.99 (m, 27H, TBS t-Bu, TES CH₃), 1.22 (s, 3H, CH₃), 1.25 (s,3H, CH₃), 1.33 (s, 3H, CH₃), 1.75 (dt, J=11.6, 1.6 Hz, 1H), 1.85 (d,J=3.3 Hz, 1H), 1.90 (t, J=3.9 Hz, 1H), 1.97 (t, J=8.1 Hz, 1H), 2.00 (s,3H, CH₃), 2.30 (m, 1H), 2.39-2.60 (m, 3H), 2.65 (m, 1H), 3.35 (dd,J=9.6, 7.8 Hz, 1H, H7α), 4.35 (dd, J=10.8, 3.3 Hz, 1H, H10β), 4.57 (d,J=5.1 Hz, 1H, H2β), 4.72 (m, 1H, H13β).

Ketone 18 (P₇=BOM). To a stirred solution of ketone 18 (P₇=MOP, P₁₀=TES,P₁₃=TBS) (293 mg, 0.43 mmol) in THF (28.6 mL) and methanol (9.5 mL)under nitrogen at room temperature was added dropwise 0.20 mL of a 0.1 Msolution of PPTS in CH₂Cl₂ (0.02 mmol). The reaction mixture was stirredfor 3 h, poured into 100 mL of a saturated aqueous NaHCO₃ solution andextracted with two 100 mL portions of ethyl acetate. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield 274 mg of the hydroxyketone 18 (P₇=H) as a colorless oil. This material was used withoutfurther purification.

18 (P₇=H, P₁₀=TES, P₁₃=TBS): mp 75-77° C., ¹H NMR (500 MHz, CDCl₃) δ0.10 (s, 3H, TBS CH₃), 0.13 (s, 3H, TBS CH₃), 0.61 (q, J=8.2 Hz, 6H, TESCH₂), 0.93 (s, 9H, TBS t-Bu), 0.95 (t, J=7.7 Hz, 9H, TES CH₃), 1.19 (s,3H, CH₃ 19), 1.22 (s, 3H, CH₃ 17), 1.35 (s, 3H, CH₃ 16), 1.84 (dd,J=13.7, 4.1 Hz, 1H, H9α), 1.88 (m, 2H, H9β, OH7), 1.92 (m, 1H, H6β),2.05 (d, J=1.4 Hz, 3H, CH₃ 18), 2.10 (m, 1H, H6α), 2.36 (dddd, J=1.4,4.1, 9.9, 14.4 Hz, 1H, H5α), 2.47 (dd, J=8.9, 15.4 Hz, 1H, H14β), 2.51(m, 1H, H5β), 2.54 (dd, J =4.8, 15.4 Hz, 1H, H14β), 2.86 (d, J=5.5 Hz,1H, H3), 3.59 (ddd, J=4.5, 6.2, 11.3 Hz, 1H, H7), 4.38 (dd, J=4.1, 9.1Hz, 1H, H10), 4.56 (d, J=5.5 Hz, 1H, H2), 4.69 (ddd, J =1.4, 4.8, 9.3 Hz1H, H13). Anal. Calcd. for C₃₂H₅₆O₇Si₂×0.5H₂O: C, 62.19; H, 9.30. FoundC, 62.16; H, 9.22.

To a stirred solution of hydroxy ketone 18 (P₇=H) (179 mg, 0.29 mmol) inCH₂Cl₂ (9.5 mL), diisopropylethylamine (1.49 mL, 8.6 mmol) andtetrabutylammonium iodide (253 mg, 0.69 mmol) under nitrogen was addeddropwise benzyloxymethylchloride (0.42 mL, 2.86 mmol). The reactionmixture was brought to reflux for 32 h, cooled to room temperature,poured into 100 mL of a saturated aqueous NaHCO₃ solution and extractedwith two 100 mL portions of 50% ethyl acetate in hexanes. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield 249 mg of the hydroxyketone as a yellowish oil. This material was purified by silica gelchromatography to yield 196 mg (92%) of ketone 18 (P₇=BOM, P₁₀=TES,P₁₃=TBS) as a colorless oil.

18 (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H,TBS CH₃), 0.13 (s, 3H, TBS CH₃), 0.59 (q, J=7.7 Hz, 6H, TES CH₂), 0.94(s, 9H, TBS t-Bu), 0.94 (t, J=7.7 Hz, 9H, TES CH₃), 1.22 (s, 3H, CH₃17), 1.31 (s, 3H, CH₃ 19), 1.33 (s, 3H, CH₃ 16), 1.87 (dd, J=12.1, 3.8Hz, 1H, H9α), 1.98 (d, J=1.4 Hz, 3H, CH₃ 18), 1.99 (m, 2H, H6β, H9β),2.21 (m, 1H, H6α), 2.34 (dd, J=10.4, 12.1 Hz, 1H, H5α), 2.43 (dd, J=9.3,15.4 Hz, 1H, H14α), 2.55 (ddd, J=5.5, 11.0, 13.7 Hz, 1H, H5β), 2.62 (dd,J=5.0, 15.4 Hz, 1H, H14β), 2.74 (d, J=5.0 Hz, 1H, H3), 3.38 (dd, J=6.6,11 Hz, 1H, H7), 4.38 (dd, J =3.8, 10.4 Hz, 1H, H10), 4.56 (d, J=5.0 Hz,1H, H2), 4.58 (d, J=11.5 Hz 1H, CH ₂Ph), 4.64 (d, J=11.5 Hz 1H, CH ₂Ph),4.68 (m, 2H, H13, OCH₂O), 4.82 (d, J=7.2 Hz 1H, OCH₂O), 7.31 (m, 5H,Ph).

Ketone 22a (P₅=TMS). To a vigorously stirred solution of ketone 18(P₇=BOM, P₁₀=TES, P₁₃=TBS) (315 mg, 0.42 mmol) in THF (10.5 mL),triethylamine (0.88 mL, 6.3 mmol) and trimethylsilyl chloride (0.53 mL,4.2 mmol) under nitrogen at −78° C. was added dropwise down the side ofthe flask 1.35 mL of a 0.5 M solution (0.68 mmol) of LDA in THF. After25 min, 2 mL of a saturated aqueous NaHCO₃ solution was added. Thereaction mixture was diluted with 150 mL of hexanes and washed with 20mL of a saturated aqueous NaHCO₃ solution and brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The resultingoil was filtered through celite with hexanes and the filtrate wasconcentrated under reduced pressure to give 338 mg (99%) of the TMS enolether 21a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₄=TMS) as a colorless oil. To avigorously stirred solution of TMS enol ether 21a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₄=TMS) (224 mg, 0.274 mmol) in hexanes (2.8 mL) under nitrogen atroom temperature was added dropwise 14.9 mL of a 0.02 M solution (0.30mmol) of MCPBA in hexanes. After 5 h, 2 mL of a saturated aqueous NaHCO₃solution and 2 mL of a 10% aqueous Na₂S₂O₃ solution were added. Thereaction mixture was diluted with 150 mL of ethyl acetate and washedwith 20 mL of a saturated aqueous NaHCO₃ solution, 20 mL of a 10%aqueous Na₂S₂O₃ solution, 20 mL of a saturated aqueous NaHCO₃ solutionand brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give 231 mg of the crude material as a colorless oil. Thismaterial was used without further purification, or, alternatively, waspurified by flash chromatography on silica gel to give 168 mg (74%) of22a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS) along with a mixture (15%) of 21aand 18 which could be recycled.

22a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS): mp 50.5-52° C., ¹H NMR (500 MHz,CDCl₃) δ 0.10 (s, 3H, TBS CH₃), 0.13 (s, 9H, TMS CH₃), 0.14 (s, 3H, TBSCH₃), 0.59 (q, J =8.2 Hz, 6H, TES CH₂), 0.94 (s, 9H, TBS t-Bu), 0.94 (t,J=8.2 Hz, 9H, TES CH₃), 1.24 (s, 3H, CH₃ 17), 1.32 (s, 3H, CH₃ 19), 1.33(s, 3H, CH₃ 16), 1.82 (dd, J=11.3, 13.7 Hz, 1H, H9α), 1.95 (d, J=1.4 Hz,3H, CH₃ 18), 1.98 (dd, J=3.4, 13.7 Hz, 1H, H9β), 2.16 (ddd, J =6.2, 7.2,13.3 Hz, 1H, H6α), 2.40 (dt, J=11.4, 13.3 Hz, 6β), 2.43 (dd, J=9.2, 15.2Hz, 1H, H14β), 2.63 (dd, J=5.5, 15.2 Hz, 1H, H14α), 2.74 (d, J=5.5 Hz,1H, H3α), 3.40 (dd, J=7.2, 10.6 Hz, 1H, H7α),4.36 (dd, J=3.4, 11.3 Hz,1H, H10β), 4.40 (dd, J=6.2, 12.0 Hz, 1H, H5α), 4.54 (d, J=5,5 Hz, 1H,H2β), 4.57 (d, J=11.7 Hz 1H, CH ₂Ph), 4.64 (d, J =11.7 Hz 1H, CH ₂Ph),4.68 (d, J=7.0 Hz 1H, OCH₂O), 4.74 (m, 1H, H13), 4.78 (d, J=7.0 Hz, 1H,OCH₂O), 7.31 (m, 5H, Ph). Anal. Calcd. for C₄₃H₇₂O₉Si₃: C, 63.19; H,8.88. Found C, 63.19; H, 8.92.

Ketone 22a (P₅=H). To a vigorously stirred solution of crude 22a(P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS) (231 mg, 0.274 mmol) in acetonitrile(7 mL) at 0° C. was added dropwise 7 mL of a 1:10:10 (by volume) mixtureof 48% aqueous HF:pyridine:acetonitrile. After stirring for 20 min, 2 mLof a saturated aqueous NaHCO₃ solution was added. The reaction mixturewas diluted with 150 mL of ethyl acetate and washed with 30 mL of asaturated aqueous NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to give 223 mg of the crudealcohol as a colorless oil. This material was purified by silica gelchromatography to yield 155 mg (74%) of ketone 22a (P₇=BOM, P₁₀=TES,P₁₃=TBS, P₅=H), 15 mg (7%) of the 5β-hydroxy ketone and 33 mg (14%recoverable material) of a 1:1 mixture of TMS enol ether 21a and ketone18.

22a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=H): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s,3H, TBS CH₃), 0.14 (s, 3H, TBS CH₃), 0.59 (q, J=8.2 Hz, 6H, TES CH₂),0.94 (s, 9H, TBS t-Bu), 0.94 (t, J=8.2 Hz, 9H, TES CH₃), 1.23 (s, 3H,CH₃ 19), 1.32 (s, 3H, CH₃ 17), 1.33 (s, 3H, CH₃ 16), 1.83 (dd, J=11.0,13.7 Hz, 1H, H6β), 1.97 (d, J=1.4 Hz, 3H, H18), 2.01 (dd, J=3.2, 13.7Hz, 1H, H9β), 2.11 (ddd, J=5.5, 7.7, 13.7 Hz, 1H, H6α), 2.47 (dd, J=8.7,15.4 Hz, 1H, H14β), 2.57 (m, 2H, H14α, H9α), 2.88 (d, J=5.5 Hz, 1H,H3α), 3.39 (dd, J=7.7, 11.0 Hz, 1H, H7α), 3.41 (d, J=3.3 Hz, 1H, OH-5),4.38 (m, 2H, H5β,H10), 4.55 (d, J =5.5 Hz, 1H, H2β), 4.57 (d, J=11.5 Hz1H, CH ₂Ph), 4.62 (d, J=11.5 Hz 1H, CH ₂Ph), 4.72 (m, 2H, H13β, OCH₂O),4.80 (d, J=7.1 Hz 1H, OCH₂O), 7.31 (m, 5H, Ph).

Ketone 22a (P₅=TMS) from ketone 22a (P₅=H). To a vigorously stirredsolution of 5-hydroxy-4ketone 22a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=H) (51mg, 0.067 mmol) in CH₂Cl₂ (2.2 mL) and triethylamine (0.14 mL, 1.0 mmol)under nitrogen at 0° C. was added trimethylsilylchloride (0.041 mL, 0.34mmol). After 0.5 h, the reaction mixture was quenched with 5 mL of asaturated aqueous NaHCO₃ solution and extracted with 150 mL hexanes. Theorganic phase was washed with 50 miL of a saturated aqueous NaHCO₃solution and brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give 56 mg a colorless oil. This material wasfiltered through silica gel and the filtrate was concentrated underreduced pressure to yield 54 mg (96%) of ketone 22a (P₇=BOM, P₁₀=TES,P₁₃=TBS, P₅=TMS).

Alcohol 23a. To a stirred solution of ketone 22a (P₇=BOM, P₁₀=TES,P₁₃=TBS, P₅=TMS) (18.9 mg, 0.023 mmol) in CH₂Cl₂ (4 mL) under nitrogenat −65° C. was added dropwise a 0.073 mL of a 3.1 M solution of MeMgBrin ether (0.23 mmol). The reaction mixture was allowed to warm to −48°C., stirred for 16.5 h and then quenched with 0.13 mL of a 2.0M solutionof AcOH in THF (0.25 mmol) and then poured into a stirring mixture of 50mnL of a saturated aqueous NaHCO₃ solution and 50 mL of ethyl acetate.The aqueous phase was extracted with 50 mL ethyl acetate. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield 20.5 mg of a colorless oil.This material was purified by silica gel chromatography to yield 18.4 mg(95%) of alcohol 23a (P₇=BOM, P₁₀=TES, P₁₃ =TBS, P₅=TMS) as a colorlessoil.

23a (P₇=BOM, P₁₀=TES, P₁₃=TBS, P₅=TMS): ¹H NMR (500 MHz, CDCl₃) δ 0.09(s, 9H, TMS), 0.11 (s, 3H, TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.56 (q,J=7.9 Hz, 6H, TES CH₂), 0.92 (t, J=7.9 Hz, 9H, TES CH₃), 0.93 (s, 9H,TBS t-Bu), 1.25 (s, 3H, CH₃ 17), 1.28 (s, 3H, CH₃ 19), 1.33 (s, 3H, CH₃20), 1.34 (s, 3H, CH₃ 16), 1.74 (ddd, J=3.8, 4.1, 13.0 Hz, 1H, H6α),1.99 (d, J=1.4 Hz, 3H, H18), 2.01 (dd, J=11.3, 13.0 Hz, 1H, H9α), 2.06(m, 2H, H3, H9β), 2.13 (ddd, J=1.7, 12.3, 13.0 Hz, 1H, H6β), 2.37 (dd,J=5.5, 15.0 Hz, 1H, H14α), 2.54 (dd, J=9.2, 15.0 Hz, 1H, H14β), 2.96 (s,1H, OH-4), 3.51 (dd, J=1.7, 4.1 Hz, 1H, H5), 3.73 (dd, J=3.8, 12.3 Hz,1H, H7α), 4.32 (dd, J=4.1, 11.3 Hz, 1H, H10β), 4.64 (s, 2H, CH ₂Ph),4.72 (d, J=6.8 Hz, 1H, OCH₂O), 4.80 (m, 3H, H2, H13, OCH₂O), 7.31 (m,5H, Ph). Anal. Calcd. for C₄₄H₇₆O₉Si₃: C, 63.42; H, 9.19. Found C,63.40; H, 9.15.

Hydroxy olefin 24a. To a refluxing solution of alcohol 23a (P₇=BOM,P₁₀=TES, P₁₃=TBS, P₅=TMS) (46.7 mg, 0.055 mmol) in toluene (1.1 mL) wasadded 1.1 mL of a 0.1M solution of Burgess reagent in toluene (0.11mmol). The mixture was refluxed for 20 min then cooled to roomtemperature, diluted with ethyl acetate, washed with a saturatedsolution of NaHCO₃ and brine, dried over anhydrous Na₂SO₄ and filtered.Concentration of the filtrate under vacuum yielded 46 mg of crudeolefin. This material was used without further purification. To astirred solution of this crude olefin (46 mg, 0.055 mmol) inacetonitrile (2.5 mL) at 0° C. was added 2.5 mL of a 1:10:10 (by volume)mixture of 48% aqueous HF: pyridine: acetonitrile. The mixture wasstirred at 0° C. for 20 min, quenched with a saturated solution ofNaHCO₃ and extracted twice with ethyl acetate. The combined organicphases were washed with brine, dried over anhydrous Na₂SO₄ and filtered.Concentration of the filtrate under vacuum yielded 48 mg of a colorlessoil which was purified by silica gel chromatography to yield 25.9 mg(62%) of hydroxy olefin 24a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=H) as well as2.1 mg of unreacted alcohol 23a (4%).

24a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=H): mp 66-68° C. ¹H NMR (500 MHz,CDCl₃) δ 0.12 (s, 3H, TBS CH₃), 0.13 (s, 3H, TBS CH₃), 0.59 (q, J=7.9Hz, 6H, TES CH₂), 0.94 (t, J=7.9 Hz, 9H, TES CH₃), 0.95 (s, 9H, TBSt-Bu), 1.18 (s, 3H, CH₃ 19), 1.23 (s, 3H, CH₃ 17), 1.35 (s, 3H, CH₃ 16),1.73 (d, 1H, J=3.4 Hz, OH5), 1.83 (dd, J=9.9, 10.5 Hz, 1H, H9α), 1.91(ddd, J=7.2, 7.5, 13.4 Hz, 1H, H6α), 1.97 (dd, J=3.8, 9.9 Hz, 1H, H9β),2.03 (d, J=1.4 Hz, 3H, 18), 2.14 (ddd, J=9.6, 9.6, 13.4 Hz, 1H, H6β)2.35 (dd, J=5.1, 15.4 Hz, 1H, H14α), 2.50 (dd, J=9.6, 15.4 Hz, 1H,H14β), 3.03 (d, J=5.8 Hz, 1H, H3α), 3.44 (dd, J=7.5, 9.6, Hz, 1H, H7α),4.38 (m, 2H, H10, H5), 4.54 (d, J=5.8 Hz, 1H, H2), 4.58 (d, J =11.6 Hz,1H, CH ₂Ph), 4.62 (d, J=11.6 Hz, 1H, CH ₂Ph), 4.73 (d, J=7.0 Hz, 1H,OCH₂O), 4.75 (m, 1H, H13), 4.79 (d, J=7.0 Hz, 1H, OCH₂O), 5.00 (s, 1H,H20E), 5.18 (s, 1H, H20Z), 7.31 (m, 5H, Ph). Anal. Calcd. forC₄₁H₆₆O₈Si₂×0.5H₂O: C, 65.47; H, 8.98. Found C, 65.63; H, 8.97.

Allyl mesylate 24aa. To a stirred solution of allyl alcohol 24a (P₇=BOM,P₁₀=TES, P₁₃=TBS, R=H) (11.5 mg, 0.0154 mmol) in pyridine (0.6 mL) undernitrogen at 0° C. was added dropwise methanesulfonyl chloride (0.02 mL,0.258 mmol). After 45 min, a saturated aqueous NaHCO₃ solution (0.05 mL)was added. The mixture was stirred for 10 min, poured into 20 mL of asaturated aqueous NaHCO₃ solution and extracted with 40% ethylacetate/hexane (20 mL×3). The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 13 mgof 24aa (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms) as a colorless oil. Thismaterial was used without further purification.

24aa (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms): ¹H NMR (300 MHz, CDCl₃); δ 0.12(s, 3H, TBS CH₃), δ 0.13 (s, 3H, TBS CH₃), 0.58 (q, J=7.9 Hz, 6H, TESCH₂), 0.93 (s, 9H, TBS t-Bu), 0.94 (t, J=7.9 Hz, 9H, TES CH₃), 1.23 (s,3H, CH₃ 17), 1.22 (s, 3H, CH₃ 19), 1.34 (s, 3H, CH₃ 16), 1.80 (br t,J=13 Hz, 1H, H9α), 1.98 (m, 1H, H6), 1.79 (ddd, J=2.2, 5.5, 15.1 Hz, 1H,H14α), 2.01 (d, J=1.1 Hz, 1H, CH₃18), 2.06 (dd, J=3.3, 13.7 Hz, 1H,H9β), 2.01 (br s, 3H, CH3 18), 2.22-2.32 (m, 3H, H14α, H6α, H6β), 2.54(dd, J=9.9, 15.4 Hz, 1H, H14β), 3.02 (s, 3H, OSO₂CH₃), 3.05 (d, J=6.0Hz, 1H, H3α), 3.45 (t, J=8.5 Hz, 1H, H7α), 4.37 (dd, J=3.6, 11.0 Hz, 1H,H10β), 4.57 (d, J=6.0 Hz, 1H, H2β), 4.59 (q, 2H, PhCH ₂O), 4.69 (d,J=7.1 Hz, 1H, OCH₂O), 4.74 (m, 1H, H13β), 4.76 (d, J=7.1 Hz, 1H, OCH₂O),5.03 (br t, J=8.5 Hz, 1H, H5β), 5.09 (br s, 1H, H20), 5.24 (br s, 1H,H20), 7.35 (m, 5H, Ph).

Triol 25a. To a stirred solution of allyl alcohol 24a (P₇=BOM, P₁₀=TES,P₁₃=TBS, R=H) (45 mg, 0.0606 mmol) in a mixture of pyridine (0.32 mL)and ether (3.2 mL) under nitrogen at 0° C. was added a 0.157 M solutionof OsO₄ in THF (0.42 mL, 0.066 mmole). After 12 h at 0° C., NaHSO₃ (530mg), pyridine (0.3 mL), THF (2 mL) and water (3 mL) were added. Themixture was vigorously stirred at room temperature for 14 h, poured into50 mL of a saturated aqueous NaHCO₃ solution and extracted with ethylacetate (40 mL×3). The combined organic phase was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give 60 mg of a paleyellow oil, which was column chromatographed (30% ethyl acetate/hexane)to yield 34.3 mg (73%) of triol 25a (P₇=BOM, P₁₀=TES, P₁₃=TBS).

25a (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.11 (s, 6H,TBS CH₃), 0.60 (ddd, J=9.0 Hz, 6H, TES CH₂), 0.79 (s, 3H, CH₃ 19), 0.93(s, 9H, TBS t-Bu), 0.94 (dd, J=9.0 Hz, 9H, TES CH₃), 1.22 (s, 3H, CH₃17), 1.35 (s, 3H, CH₃ 16), 1.64 (dd, J=5.6, 16.4 Hz, 1H, H9β), 1.70 (m,1H, H6β), 2.22 (dd, J=2.7, 16.8 Hz, 1H, H9α), 2.23 (d, J =0.7 Hz, 3H,CH₃ 18), 2.36 (dd, J=9.2, 15.0 Hz, 1H, H14β), 2.45 (m, 1H, H6α), 2.96(s, 1H, OH5), 3.21 (dd, 6.9, 15.0 Hz, 1H, H14α), 3.42 (d, J=5.0 Hz, 1H,H3α), 3.53 (m, 1H, H20), 3.38 (s, 1H, OH4), 3.70 (t, J=3.0 Hz, 1H, H5β),4.04 (br d, J=11 Hz, 1H, H20), 4.06 (dd, J=11.5, 5.0 Hz, 1H, H7α), 4.48(d, J=5.0 Hz, 1H, H2β), 4.49 (d, J=12.0 Hz, 1H, PhCH ₂O), 4.53 (br s,1H, H10β), 4.71 (m, 1H, H13β), 4.72 (d, J=12.0 Hz, 1H, PhCH ₂O), 4.85(d, J=6.8 Hz, 1H, OCH₂O), 4.98 (d, J=6.8 Hz, 1H, OCH₂O), 7.34 (m, 5H,Ph). Anal. Calcd. for C₄₁H₆₈O₁₀Si₂: C, 63.36; H, 8.82. Found C, 63.19;H, 8.75.

Diol mesylate 26a. To a stirred solution of allyl mesylate 24aa (P₇=BOM,P₁₀=TES, P₁₃=TBS, R=Ms) (5 mg, 0.0064 mmol) in a mixture of pyridine(0.4 mL) and THF (0.4 mL) under nitrogen at room temperature was added a0.157 M solution of OsO₄ in THF (0.06 mL). After 7 h, NaHSO₃ (150 mg)and water (0.2 mL) were added. The mixture was vigorously stirred for 14h, poured into 20 mL of a saturated aqueous NaHCO₃ solution andextracted with ethyl acetate (20 mL×3). The combined organic phase wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive 6 mg of a pale yellow oil. The oil was column chromatographed (40%ethyl acetate/hexane) to yield 2.7 mg (50%) of diol mesylate 26a(P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms).

26a (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ms): ¹H NMR (500 MHz, CDCl₃); δ 0.14(s, 6H, TBS CH₃), 0.58 (ddd, J=8.0 Hz, 6H, TES CH₂), 0.89 (s, 3H, CH₃19), 0.93 (s, 9H, TBS t-Bu), 0.94 (dd, J=8.0 Hz, 9H, TES CH₃), 1.31 (s,3H, CH₃ 17), 1.37 (s, 3H, CH₃ 16), 1.76 (dd, J=5.5, 15.1, 1 Hz, H9β),1.95 (m, 1H, H6β), 2.23 (d, J=0.7 Hz, 3H, CH₃ 18), 2.25 (dd, J=4.8, 15.1Hz, 1H, H9 α), 2.39 (dd, J=9.2, 15.1 Hz, 1H, H 14β), 2.45 (m, 1H, H6α),2.89 (dd, 6.8, 15.1 Hz, 1H, H14α), 3.05 (d, J=3.4 Hz, 1H, H3α), 3.06 (s,3H, OSO₂CH₃), 3.35 (s, 1H, OH4), 3.52 (m, 1H, H20), 3.92 (dd, J=4.5,11.6 Hz, 1H, H7α), 4.13 (dd, J=1.0, 11.3 Hz, 1H, H20), 4.46 (br d, J=4.5Hz, 1H, H10), 4.52 (d, J=3.4 Hz, 1H, H2), 4.54 (d, J=12.0 Hz, 1H, PhCH₂O), 4.70 (d, J=12.0 Hz, 1H, PhCH ₂O), 4.83 (d, J=6.9 Hz, 1H, OCH₂O),4.84 (m, 1H, H5β), 4.92 (m, 1H, H13β), 4.93 (d, J=6.9 Hz, 1H, OCH₂O),7.34 (m, 5H, Ph).

Diol tosylate 26aa. To a stirred solution of triol 25a (P₇=BOM, P₁₀=TES,P₁₃=TBS) (37 mg, 0.0476 mmole) in CH₂Cl₂ (0.4 mL) under nitrogen at −78° C. was added triethylamine (0.25 mL) followed by trimethylchlorosilane(0.075 mL). The solution was stirred at −78° C. for 1 h, poured into 20mL of a saturated aqueous NaHCO₃ solution and extracted with chloroform(30 mL ×3). The combined organic phase was dried over anhydrous Na₂SO₄,and concentrated under reduced pressure to give 38.2 mg of a colorlessoil. This oil was dissolved in THF (0.5 mL) and cooled to −78° C. Tothis solution was added a 0.2 M solution of LDA in THF (0.9 mL, 0.18mmole). After 20 min at −78° C., p-toluenesulfonyl chloride (35 mg,0.183 mmole) was added. After stirring at −35° C. for 3 h, MeOH (0.2 mL)and diethylamine (0.3 mL) were added. The solution was stirred at −35°C. for 30 min and poured into 30 mL of a saturated aqueous NaHCO₃solution and extracted with chloroform (40 mL×3). The combined organicphases were dried over anhydrous Na₂SO₄, and concentrated under reducedpressure to give 58 mg of a colorless oil. The oil was dissolved inacetonitrile (3.6 mL) and pyridine (3.6 mL). To this solution at 0° C.was added 48% aqueous solution of HF (0.36 mL). The solution was stirredat 0° C. for 15 min, poured into 30 mL of a saturated aqueous NaHCO₃solution and extracted with chloroform (40 mL×3). The combined organicphase was dried over anhydrous Na₂SO₄, and concentrated under reducedpressure to give 56 mg of crude diol tosylate 26aa. Columnchromatography (40% ethylacetate/hexane) yielded 34 mg (80%) dioltosylate 26aa (P₇=BOM, P₁₀=TES, P₁₃=TBS, R=Ts).

26aa (P₇=BOM, P₁₀ TES, P₁₃=TBS, R=Ts). ¹H NMR (300 MHz, CDCl₃); δ 0.18(s, 6H, TBS CH₃), 0.58 (d, J=12.5 Hz, 6H, TES CH₂), 0.82 (s, 3H, CH₃19), 0.94 (dd, J=13.0 Hz, 9H, TES CH₃), 0.97 (s, 9H, TBS t-Bu), 1.28 (s,3H, CH₃ 17), 1.34 (s, 3H, CH₃ 16), 1.67 (dd, J=16.5, 4.4 Hz, 1H, H9β),1.80 (m, 1H, H6β), 2.13 (dd, J=16.5, 4.4 Hz, 1H, H9α), 2.18 (m, 1H,H6α), 2.24 (s, 3H, CH₃ 18), 2.33 (s, 3H, CH₃Ph), 2.42 (dd, J=14.8, 9.3Hz, 1H, H14β), 2.90 (m, 1H, H14α), 2.93 (br s, 1H, OH4), 3.08 (br d,J=3.3 Hz, 1H, H3α), 3.38 (br t, J=11.0 Hz, 1H, H7α), 3.87 (m, 1H, H20),4.09 (br d, J=9.9 Hz, 1H, H20), 4.52 (d, J=3.3 Hz, 1H, H2β), 4.45 (br d,J=4.4 Hz, 1H, H10β), 4.46 (d, J=12.1 Hz, 1H, PhCH ₂O), 4.59 (d, J=12.1Hz, 1H, PhCH ₂O), 4.66 (br t, J=3.8 Hz, 1H, H5β), 4.75 (d, J=7.1 Hz, 1H,OCH₂O), 4.83 (d, J=7.1 Hz, 1H, OCH₂O), 4.89 (br dd, J=7.7, 6.6 Hz, 1H,H13β), 7.14 (d, J=8.2 Hz, 2H, SO₂Ph), 7.34 (m, 5H, OCH₂ Ph), 7.75 (d,J=8.2 Hz, 2H, SO₂Ph).

Oxetane 27a from diol mesylate 26a. To a stirred solution of diolmesylate 26a (P₇=BOM, P₁₀ =TES, P₁₃=TBS, R=Ms) (2.7 mg) in toluene (0.4mL) under nitrogen at room temperature was added diisopropyl ethylamine(0.008 mL). The solution was refluxed for 3.5 h, cooled to roomtemperature, poured into 20 mL of a saturated aqueous NaHCO₃ solutionand extracted with ethyl acetate (20 mL×3). The combined organic phasewas dried over anhydrous Na₂SO₄, and concentrated under reduced pressureto give 3 mg of a pale yellow oil. The oil was column chromatographed(30% ethyl acetate/hexane) to yield 1 mg (42%) of oxetane 27a.

27a (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.10 (s, 6H,TBS CH₃), 0.59 (dd, J=8.0 Hz, 6H, TES CH₂), 0.92 (s, 9H, TBS t-Bu), 0.94(dd, J=8.0 Hz, 9H, TES CH₃), 1.20 (s, 3H, CH₃ 17), 1.26 (s, 3H, CH₃ 19),1.32 (s, 3H, CH₃ 16), 1.93 (dd, J=11.3, 13.4 Hz, 1H, H9α), 1.98 (d,J=1.4 Hz, 3H, CH₃ 18), 2.06 (dd, J=6.0, 18.6 Hz, 1H, H6β), 2.11 (dd,J=4.5, 13.4 Hz, 1H, H90β), 2.14 (d, J=5.5 Hz, 1H, H3α), 2.41 (dd, J=9.2,15.1 Hz, 1H, H14 β), 2.43 (m, 1H, H6α), 2.54 (s, 1H, OH4), 2.76 (dd,J=5.2, 15.1 Hz, H14α), 3.21 (dd, J=3.4, 13.0 Hz, 1H, H7α), 4.36 (d,J=8.6 Hz, 1H, H20α), 4.37 (dd, J=4.1, 11.3 Hz, 1H, H10β), 4.40 (br d,J=8.2 Hz, 1H, H5α), 4.60 (d, J=5.5 Hz, 1H, H2β), 4.61 (d, J=12.6 Hz, 1H,PhCH ₂O), 4.67 (m, 1H, H13β), 4.69 (d, J=12.6 Hz, 1H, PhCH ₂O), 4.75 (d,J=7.5 Hz, 1H, OCH₂O), 4.86 (d, J=7.5 Hz, 1H, OCH₂O), 4.91 (dd, J=0.7,8.6 Hz, 1H, H20β), 7.34 (m, 5H, Ph). Anal. Calcd. for C₄₁H₆₆O₉Si₂: C,64.87; H, 8.76. Found C, 64.61; H, 8.78.

Oxetane 27a from diol tosylate 26aa. To a stirred solution of dioltosylate 26aa (P₇=BOM, P₁₀ =TES, P₁₃=TBS, R=Ts) (33 mg, 0.0354 mmole) intoluene (3.3 mL) under nitrogen at room temperature was added DBU (0.11mL, 0.73 mmole). The solution was heated at 80° C. for 10 min, then thetemperature was increased up to 110° C. during a 40 min period,maintained at 110° C. for 30 more min and cooled to room temperature.The solution was filtered through a short pad of silica gel using 30%ethyl acetate/hexane as eluent. The filtrate was concentrated to give 25mg of crude 27a, which was column chromatographed (30% ethylacetate/hexane) to yield 21 mg (78%) of oxetane 27a (P₇=BOM, P₁₀=TES,P₁₃=TBS).

Oxetane 29. To a stirred solution of oxetane 27a (P₇=BOM, P₁₀=TES,P₁₃=TBS) (21 mg, 0.0276 mmloe) and dimethylaminopyridine (3.4 mg, 0.0278mmole) in pyridine (110 μL, 1.37 mmole) under nitrogen at roomtemperature was added acetic anhydride (26 μL, 0.276 mmole).

The solution was stirred for 25 h, diluted with ethyl acetate, pouredinto 20 mL of saturated aqueous NaHCO₃ solution and extracted with ethylacetate (20 mL×3). The combined organic phases were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give 26 mg of a paleyellow oil, which was column chromatographed (25% ethyl acetate/hexane)to yield 16 mg (72%) of oxetane 29 (P₇=BOM, P₁₀=TES, P₁₃=TBS).

29 (P₇=BOM, P₁₀=TES, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.10 (s, 3H,TBS CH₃), 0.12 (s, 3H, TBS CH₃), 0.56 (q, 6H, TES CH₂), 0.92 (t, 9H, TESCH₃), 0.94 (s, 9H, TBS t-Bu), 1.35 (s, 3H, CH₃ 16), 1.30 (s, 3H, CH₃17), 1.29 (s, 3H, CH₃ 19), 1.96 (br t, J=13.0 Hz, 1H, H9α), 1.98 (d,J=1.4 Hz, 3H, CH₃ 18), 2.02 (dd, J=7.5, 13.0, 1H, H9β), 2.07 (dt, J=8.0,13.0 Hz, 1H, H6β), 2.13(s, 3H, OAc), 2.24 (dd, J=3.4, 15.0 Hz, 1H,H14α), 2.40 (dd, J=8.6, 15.0 Hz, 1H, H14β), 2.51 (ddd, J=4.1, 9.2, 15.0Hz, 1H, H6α), 2.63 (d, J=6.5 Hz, 1H, H3α), 3.69 (dd, J=4.1, 13.0 Hz,H7α), 4.35 (dd, J=3.4, 11.3 Hz, 1H, H10β), 4.64 (m, 4H, PhCH ₂O, H2β,H5α), 4.75 (d, J=7.2 Hz, 1H, OCH₂O), 4.76 (br d, J =9.2 Hz, 1H, H20),4.83 (d, J=7.2 Hz, 1H, OCH₂O), 4.85 (br d, J=9.2 Hz, 1H, H20), 4.88 (brt, J=8.2 Hz, 1H, H13β), 7.35 (m, 5H, Ph).

Benzoate 30. To a stirred solution of oxetane 29 (P₇=BOM, P₁₀=TES,P₁₃=TBS) (6 mg, 0.0075 mmol) in THF (0.5 mL) under nitrogen at −78° C.was added a 0.3M solution of phenyllithium in ether (44 μL, 0.013 mmol).The solution was stirred at −78° C. for 15 min and quenched with a 10%solution of acetic acid in THF. The solution was diluted with ethylacetate, poured into 20 mL of a saturated aqueous NaHCO₃ solution andextracted with ethyl acetate (20 mL×3). The combined organic phases weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive 8 mg of a pale yellow oil. The oil was column chromatographed (25%ethyl acetate/hexane) to yield 6.2 mg (94%) of benzoate 30 (P₇=BOM,P₁₃=TBS, R=TES).

30 (P₇=BOM, P₁₃=TBS, R=TES): ¹H NMR (500 MHz, CDCl₃); δ 0.09 (s, 3H, TBSCH₃), 0.14 (s, 3H, TBS CH₃), 0.60 (ddd, 6H, TES CH₂), 0.94 (s, 9H, TBSt-Bu), 0.96 (t, 6H, TES CH₃), 1.23 (s, 3H, CH₃ 17), 1.38 (s, 3H, CH₃19), 1.46 (s, 3H, CH₃ 16), 1.69 (s, 1H, OH1), 1.97 (ddd, J=14.5, 10.0,3.1 Hz, 1H, H6β), 2.05 (dd, J=16.1, 5.1 Hz, 1H, H9β), 2.09 (dd, J=15.1,6.2 Hz, 1H, H14β), 2.13 (s, 3H, CH₃ 18), 2.22 (dd, J=15.1, 8.2 Hz, 1H,H14α), 2.23 (dd, J=15.0, 8.5 Hz, 1H, H9β), 2.24 (s, 1H, OAc 4), 2.38(dd, J=16.1, 4.1 Hz, 1H, H9α), 2.67 (m, 1H, H6α), 3.40 (d, J=6.2 Hz, 1H,H3α), 3.99 (dd, J=10.1, 6.8 Hz, 1H, H7α), 4.20 (d, J=8.2 Hz, 1H, H20β),4.29 (d, J=8.2 Hz, 1H, H20α), 4.49 (d,J=12.0 Hz, 1H, PhCH ₂O), 4.63 (brt, 1H, H10β), 4.74 (d, J=12.0 Hz, 1H, PhCH ₂O), 4.92 (d, J=6.9 Hz, 1H,OCH₂O), 4.91-4.95 (m, 2H, H13β & H5α), 5.01(d, J=6.9 Hz, 1H, OCH₂O),5.66 (d, J=6.2 Hz, 1H, H2β), 7.28 (m, 1H, PhCH₂), 7.35 (m, 4H, PhCH₂),7.48 (m, 2H, PhCOO -m), 7.59 (m, 1H, PhCOO -p), 8.11 (m, 2H, PhCOO-o).

Alcohol 31. To a solution of benzoate 30 (P₇=BOM, P₁₃=TBS, R=TBS) (6.2mg, 0.007 mmol) in 2 mL of THF was added 0.1 mL of a 0.1 M solution ofTBAF in THF. The mixture was stirred for 2 h at 25° C. under nitrogen.The reaction mixture was diluted with 10 mL of ethyl acetate, thenpoured into 10 mL of a saturated aqueous NaHCO₃ solution. The organicphase was washed with 10 mL of a saturated aqueous NaHCO₃ solution,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive 4.5 mg (93%) of alcohol 31 (P₇ =BOM, P₁₃=TBS, R=H).

31 (P₇=BOM, P₁₃=TBS, R=H): mp 213-216° C. ¹H NMR (500 MHz, CDCl₃); δ0.10 (s, 3H, TBS CH₃), 0.15 (s, 3H, TBS CH₃), 0.94 (s, 9H, TBS t-Bu),1.26 (s, 3H, CH₃ 17), 1.39 (s, 3H, CH₃ 19), 1.45 (s, 3H, CH₃ 16), 1.68(s, 1H, OH1), 1.89 (ddd, J=14.5, 10.0, 2.5 Hz, 1H, H6β), 2.10 (dd,J=15.0, 9.0 Hz, 1H, H14β), 2.15 (dd, J=15.0, 8.0 Hz, 1H, H14α), 2.18 (s,3H, CH₃ 18), 2.23 (dd, J=15.0, 8.5 Hz, 1H, H9β), 2.26 (s, 1H, OAc 4),2.40 (dd, J=15.0, 3.5 Hz, 1H, H9α), 2.68 (m, 1H, H6α), 2.90 (br s, 1H,OH10), 3.54 (d, J=6.0 Hz, 1H, H3α), 4.16 (d, J=8.0 Hz, 1H, H20β), 4.23(dd, J=10.0, 7.0 Hz, 1H, H7α), 4.30 (d, J=8.0 Hz, 1H, H20α), 4.68(dd,J=15 Hz, 2H, PhCH ₂O), 4.78 (m, 1H, H10β), 4.87 (d, J=6.5 Hz, 1H,OCH₂O), 4.95 (t, J=2.0 Hz, 1H, H20α), 4.92 (d, J=7.0 Hz, 1H, OCH₂O),4.93 (br d, J=2.0 Hz, 1H, H13β), 4.96 (br d, J=6.5 Hz, 1H, H5α), 4.97(d, J=6.5 Hz, 1H, OCH₂O), 5.68 (d, J=6.0 Hz, 1H, H2β), 7.28 (m, 1H,PhCH₂O), 7.35 (m, 4H, PhCH₂O), 7.40 (m, 2H, PhCOO-m), 7.59 (m, 1H,PhCOO-p), 8.13 (m, 2H, PhCOO-o). Anal. Calcd. for C₄₃H₆₀O₁₀Six0.5H₂O: C,66.72; H, 7.94. Found C, 66.75; H, 7.96.

Alcohol 31 through Alcohol 30a. To a stirred solution of oxetane 29(P₇=BOM, P₁₀=TES, P₁₃=TBS) (16 mg, 0.02 mmole) in acetonitrile (0.33 mL)at 0° C. was added a 4% solution of HF-pyridine complex in acetonitrile(0.8 mL). The solution was stirred at 0° C. for 11 h, diluted with ethylacetate, poured into 20 mL of a saturated aqueous NaHCO₃ solution andextracted with CHCl₃ (30 mL×3). The combined organic phases were driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to give13.5 mg (0.0196 mmole) of 30a as an oil. This oil was dissolved in THF(1 mL) and cooled to −78° C. To this solution at −78° C. was added a0.285 M solution of phenyllithium in THF (0.144 mL, 2.1 eq.). After 10min, the solution was poured into 20 mL of saturated aqueous NaHCO₃solution and CHCl₃ (30 mL×3). The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 16 mgof a pale yellow oil, which was crystalized to yield 12.7 mg (85%) ofbenzoate 31 (P₇=BOM, P₁₃=TBS, R=H).

Ketone 32. To a solution of benzoate 31 (P₇=BOM, P₁₃=TBS, R=H) (18 mg,0.235 mmole) and 4-methylmorpholine N-oxide (18 mg, 0.154 mmole) inCH₂Cl₂ (2.6 mL) at room temperature was added tetrapropylammoniumperruthenate (6 mg, 0.017 mmole). The solution was stirred at roomtemperature for 15 min and filtered through silica gel with 30 % ethylacetate/hexane. The filtrate was concentrated under reduced pressure toyield ketobenzoate 32 (P₇=BOM, P₁₃=TBS) (18 mg, 100%).

32 (P₇=MOP, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.12 (s, 3H, TBS CH₃),0.16 (s, 3H, TBS CH₃), 0.94 (s, 9H, TBS t-Bu), 1.25 (s, 3H, CH₃), 1.42(s, 3H, CH₃), 1.44 (s, 6H, MOP CH₃), 1.49 (s, 3H, CH₃), 1.75 (s, 1H,OH1), 1.76 (m, 1H, H6), 1.83 (s, 3H, CH₃ 18), 2.21 (dd, J=7, 15 Hz, 1H,H14), 2.25 (s, 3H, OAc), 2.29 (dd, J=8, 15 Hz, 1H, H14), 2.61 (d, J=16Hz, 1H, H9), 2.74 (ddd, J=8, 9, 17 Hz, 1H, H6), 3.19 (s, 3H, MOP OCH₃),3.20 (d, J=6 Hz, 1H, H3α), 3.32 (d, J=16 Hz, 1H, H9), 3.78 (dd, J=8, 10Hz, 1H, H7), 4.15 (d, J=8 Hz, 1H, H20), 4.34 (d, J=8 Hz, 1H, H20), 4.89(d, J=9 Hz, 1H, H5), 5.04 (m, 1H, H13), 5.90 (d, J=6 Hz, 1H, H2), 7.50(m, 2H, PhCOO -m), 7.62 (m, 1H, PhCOO -p), 8.24 (m, 2H, PhCOO -o).

32 (P₇=TES, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.12 (s, 3H, TBS CH₃),0.16 (s, 3H, TBS CH₃), 0.65 (q, J=8 Hz, 3H, TES CH₃), 0.66 (q, J=8 Hz,3H, TES CH₃), 0.94 (s, 9H, TBS t-Bu), 1.00 (t, J=8 Hz, 3H, TES CH₂),1.24(s, 3H, CH₃ ), 1.38 (s, 3H, CH₃ ), 1.49 (s, 3H, CH₃), 1.75 (s, 1H,OH1), 1.80 (m, 1H, H6), 1.81 (s, 3H, CH₃ 18), 2.20 (dd, J=9, 15 Hz, 1H,H14), 2.26 (s, 3H, OAc CH₃), 2.29 (dd, J=8, 15 Hz, 1H, H14), 2.48 (ddd,J=8, 9, 17 Hz, 1H, H6), 2.58 (d, J=17 Hz, 1H, H9), 3.15 (d, J=6 Hz, 1H,H3α), 3.36 (d, J=17 Hz, 1H, H9), 3.79 (dd, J=7, 9 Hz, 1H, H7), 4.14 (d,J=8 Hz, 1H, H20), 4.33 (d, J=8 Hz, 1H, H20), 4.90 (d, J=9 Hz, 1H, H5),5.04 (m, 1H, H13), 5.90 (d, J=6 Hz, 1H, H2), 7.49 (m, 2H, PhCOO -m),7.61 (m, 1H, PhCOO -p), 8.13 (m, 2H, PhCOO -o).

32 (P₇ BOM, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃); δ 0.16 (s, 3H, TBS CH₃),0.18 (s, 3H, TBS CH₃), 0.94 (s, 9H, TBS t-Bu), 1.26 (s, 3H, CH₃ 17),1.47 (s, 3H, CH₃ 19), 1.52 (s, 3H, CH₃ 16), 1.76 (s, 1H, OH1), 1.83 (d,3H,J=0.5 Hz, CH₃ 18), 1.89 (ddd, J=15.0, 9.5, 1.5 Hz, 1H, H6β), 2.21(dd, J=15.0, 9.0 Hz, 1H, H 14β), 2.26 (s, 1H, OAc 4), 2.29 (dd, J=15.0,8.0 Hz, 1H, H14α), 2.72 (m, 1H, H6α), 2.75 (d, J=16 Hz, 1H, H9α), 3.18(d, J=6.5 Hz, 1H, H3α), 3.26 (d, J=16.5 Hz, H9α), 3.65 (dd, J=9.0, 7.5Hz, 1H, H7α), 4.15 (d, J=7.5 Hz, 1H, H20β), 4.34 (d, J=7.5 Hz, 1H,H20α), 4.61 (d,J=12.0 Hz, 1H, PhCH ₂O), 4.72 (d, J=12.0 Hz, 1H, PhCH₂O), 4.81 (d, J=7.0 Hz, 1H, OCH₂O), 4.92 (d, J=7.0 Hz, 1H, OCH₂O), 4.93(br d, J=6.5 Hz, 1H, H5α), 5.05 (br t, J=6.5 Hz, 1H, H13β), 5.91 (d,J=6.0 Hz, 1H, H2β), 7.28 (m, 1H, PhCH ₂O), 7.35 (m, 4H, PhCH ₂O), 7.50(m, 2H, PhCOO -m), 7.62 (m, 1H, PhCOO -p), 8.13 (m, 2H, PhCOO -o)

Hydroxyketone 33. To a THF (1.3 mL) solution of 32 (P₇=BOM, P₁₃=TBS)(16.2 mg, 0.02 mmol) at −78° C. was added 4 equivalents of a 0.24M t-BuOK solution in THF (0.33 mL, 0.08 mmol.). The solution was warmed to−20° C. for 40 min and then briefly warmed to 0° C. before beingcannulated into a 0° C. THF (1.3 mL) suspension of benzeneseleninicanhydride (57 mg, 0.16 mmol.). The reaction was stirred for 40 min. at0° C. before being diluted with 20 mL of ethyl acetate and poured into50 mL of aqueous saturated NaHCO₃. The organic layer was then washedwith 50 mL of aqueous saturated Na₂S₂O₃ followed by 50 mL of aqueoussaturated NaHCO₃. The organic layer was then dried with Na₂SO₄, filteredand evaporated to give 18.8 mg of the hydroxyketone as an oil. To a THF(1.3 mL) solution of the crude hydroxyketone (18.8 mg) was added 0.33 mLof a 0.24M solution of t -BuOK (0.08 mmol) at −78° C. The reaction wasstirred 20 min. and then 0.25 mL of a 0.8M AcOH/THF solution was addedat −78° C. and stirred 5 min. The mixture was diluted with 20 mL ofethyl acetate and was poured into 50 mL of aqueous saturated NaHCO₃. Theorganic layer was then dried with Na₂SO₄, filtered and evaporated togive 18.6 mg of a yellow solid which was then plug filtered throughsilica gel with 2% ethyl acetate/hexanes followed by 30% ethylacetate/hexanes to give 15.9 mg of 33 (P₇=BOM, P₁₃=TBS) (96% yield).

33 (P₇=BOM, P₁₃=TBS): m.p.: 234-236° C., ¹H NMR (500 MHz, CDCl₃) δ 0.13(s, 3H, TBS CH₃), 0.15 (s, 3H, TBS CH₃), 0.95 (s, 9H, TBS t-Bu), 1.11(s, 3H, CH₃ 16), 1.18 (s, 3H, CH₃ 17), 1.59 (s, 1H, OH1), 1.82 (s, 3H,CH₃ 18), 1.89 (ddd, J=2.1, 12.4, 14.4 Hz, 1H, H6β), 1.97 (d, J=2.0 Hz,3H, CH₃ 18), 2.14 (dd, J=8.6, 15.4 Hz, 1H, H14β), 2.21 (dd, J=8.9, 15.4Hz, 1H, H14α), 2.29 (s, 3H, Ac), 2.70 (ddd, J=6.5, 9.6, 14.4 Hz, 1H,H6α), 3.93 (d, J=6.9 Hz, 1H, H3α), 4.17 (d, J=8.6 Hz, 1H, H20β), 4.28(d, J=2.4 Hz, 1H, OH10β), 4.31 (dd, J=6.5, 12.4 Hz, 1H, H7α), 4.32 (d,J=8.6 Hz, 1H, H20α), 4.45 (d, J=12.2 Hz, 1H, PhCH ₂O), 4.60 (d, J=12.2Hz, 1H, PhCH ₂O), 4.60 (d, J=7.3 Hz, 1H, OCH₂O), 4.73 (d, J=7.3 Hz, 1H,OCH₂O), 4.97 (dd, J=2.1, 9.6 Hz, 1H, H5α), 5.01 (ddd, J=2.0, 8.6, 8.9Hz, 1H, H13β), 5.35 (d, J=2.4 Hz, 1H, H10α), 5.64 (d, J=6.9 Hz, 1H,H2β), 7.3 (m, 5H, PhCH₂), 7.49 (tt, J=1.7, 7.9 Hz, 2H, PhCOO -m), 7.61(tt, J=1.7, 7.6 Hz, 1H, PhCOO -p), 8.10 (dd, J=1.2, 7.9 Hz, PhCOO -o).

33 (P₇=MOP, P₁₃=TBS): ¹H NMR (300 MHz, CDCl₃) δ 0.13 (s, 3H, TBS CH₃),0.15 (s, 3H, TBS CH₃), 0.95 (s, 9H, TBS t-Bu), 1.00 (s, 3H, CH₃ 16),1.09 (s, 3H, CH₃ 17), 1.23 (s, 3H, MOP CH₃), 1.37 (s, 3H, MOP CH₃), 1.58(s, 1H, OH1), 1.79 (s, 3H, CH₃ 19), 1.90 (ddd, J=2.6, 8.8, 13.7 Hz, 1H,H6β), 2.04 (s, 3H, CH₃ 18), 2.13 (dd, J=8.8, 15.5 Hz, 1H, H14β), 2.22(dd, J=8.8, 15.5 Hz, 1H, H14α), 2.29 (s, 3H, OAc), 2.79 (ddd, 6.3, 9.9,14.8 Hz, 1H, H6α), 3.17 (s, 3H, MOP OCH₃), 3.90 (d, J=7.1 Hz, 1H, H3α),4.16 (d, J=8.2 Hz, 1H, H20α), 4.25 (d, J=2.2 Hz, 1H, OH4), 4.32 (d,J=8.8 Hz, 1H, H20β), 4.41 (dd, J=6.6, 11.0 Hz, 1H, H7α), 4.94 (dd,J=2.2, 9.9 Hz, 1H, H5α), 5.03 (ddd, J=1.1, 8.2, 8.8 Hz, 1H, H13β), 5.20(d, J=6.2 Hz, 1H, H10α), 5.60 (d, J=7.2 Hz, 1H, H2β), 7.48 (t, J=7.7 Hz,2H, PhCOO-m), 7.61 (t, J=7.7 Hz, 1H, PhCOO -p), 8.10 (d, J=7.1 Hz, 2H,Acetate 34. To a pyridine (0.1 mL) solution of 33 (P₇=BOM, P₁₃=TBS)(15.9 mg, 0.02 mmol) and DMAP (1.2 mg, 0.01 mmol) at room temperaturewas added acetic anhydride (38 μL, 0.4 mmol) and the reaction sirred 19h. The mixture was then diluted with 20 mL of ethyl acetate and pouredinto 50 mL of aqueous saturated NaHCO₃. The organic layer was dried withNa₂SO₄, filtered and evaporated to give 18.1 mg of crude product. Thematerial was plug filtered through silica gel with 20% ethylacetate/hexanes to give 16.8 mg of 34 (P₇=BOM, P₁₃=TBS) (100% yield).

34 (P₇=BOM, P₁₃=TBS): ¹H NMR (500 MHz, CDCl₃) δ 0.14 (s, 3H, TBS Me),0.16 (s, 3H, TBS Me), 0.95 (s, 9H, TBS t-Bu), 1.17 (s, 3H, CH₃ 17), 1.18(s, 3H, CH₃ 16), 1.63 (s, 1H, OH1), 1.76 (s, 3H, CH₃ 19), 1.99 (ddd,J=2.1, 10.6, 14.7 Hz, 1H, H6β), 2.04 (d, J=1.0 Hz, 3H, CH₃ 18), 2.17(dd, J=8.6, 15.1 Hz, 1H, H14β), 2.19 (s, 3H, AcO10), 2.24 (dd, J=8.6,15.1 Hz, 1H, H14α), 2.28 (s, 3H, AcO4), 2.88 (ddd, J=6.5, 9.8, 14.7 Hz,1H, H6α), 3.87 (d, J=7.0 Hz, 1H, H3a), 4.15 (d, J=8.2 Hz, 1H, H20β),4.24 (dd, J=6.5, 10.6 Hz, 1H, H7α), 4.31 (d, J=8.2 Hz, 1H, H20α), 4.44(d, J=12.0 Hz, 1H, PhCH ₂O), 4.68 (d, J=12.0 Hz, 1H, PhCH ₂O), 4.85 (s,2H, OCH₂O), 4.95 (dd, J=2.1, 9.8 Hz, 1H, H5α), 5.65 (d, J=7.0 Hz, 1H,H2β), 6.39 (s, 1H, H10α), 7.30 (m, 5H, PhCH₂), 7.49 (tt, J=1.4, 8.2 Hz,2H, PhCOO -m),7.61 (tt, J=1.4, 7.2 Hz, 1H, PhCOO -p), 8.05 (dd, J=1.2,8.2 Hz, 1H, PhCOO-o), IR (CHCl₃) υ 3600, 3050, 2975, 2880, 1750, 1730,1460, 1379, 1250, 1100, 1020, 860 cm⁻¹.

34 (P₇=P₁₃=TES): ¹H NMR (300 MHz, CDCl₃) δ 0.57 (q, J=7.7 Hz, 6H, TESCH₂), 0.67 (q, J=7.7 Hz, TES CH₂), 0.92 (t, J=7.7 Hz, 9H, TES CH₃), 1.01(t, J=7.7 Hz, 9H, TES CH₃), 1.11 (s, 3H, CH₃ 17), 1.19 (s, 3H, CH₃ 19),1.61 (s, 1H, OH1), 1.67 (s, 3H, CH₃ 16), 1.86 (ddd, J=2.2, 10.4, 14.3Hz, 1H, H6β), 2.11 (d, J=1.1 Hz, 3H, CH₃ 18), 2.12 (m, 1H, H14β), 2.17(s, 3H, OAc10), 2.23 (dd, J=7.6, 14.9 Hz, 1H. H14α), 2.28 (s, 3H, OAc4),2.51 (ddd, J=6.9, 9.6, 14.3 Hz, 1H, H6α), 3.82 (d, J=7.2 Hz, 1H, H3α),4.14 (d, J=8.3 Hz, 1H, H20β), 4.30 (d, J=8.3 Hz, 1H, H20α), 4.48 (dd,J=6.6, 10.4 Hz, 1H, H7α), 4.92 (dd, J=7.7, 8.8 Hz, 1H, H5α), 4.96 (d,J=8.2 Hz, 1H, H13β), 5.63 (d, J=6.6 Hz, 1H, H2α), 6.47 (s, 1H, H10α),7.47 (t, J=7.1 Hz, 2H, PhCOO -m), 7.60 (t, J=7.1 Hz, PhCOO-p), 8.10 (d,J=7.1 Hz, PhCOO -o).

Diol 35. A soluton of 34 (P₇=BOM, P₁₃=TBS) (16.3 mg, 0.0199 mmol) in THF(0.5 mL) was added totris(diethylamino)sulfoniumdifluorotrimethylsilicate (TASF) (37 mg,0.134 mmole) at room temperature under nitrogen atmosphere. The solutionwas stirred for 40 min, diluted with ethyl acetate, poured into 20 mL ofa saturated aqueous NaHCO₃ solution and extacted with CHCl₃ (30 mL×3).The combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give 16 mg of a pale yellow oil,which was filtered through a pad of silica gel using 70% ethylacetate/hexane as eluent. The filtrate was concentrated to yield 13.5 mg(94%) of 7-BOM BIII (35).

35 (P₇=BOM) mp. 224-225° C., ¹H NMR (500 MHz, CDCl₃), δ 1.08 (s, 3H, CH₃17), 1.18 (s, 3H, CH₃ 16), 1.61 (s, 1H, OH1), 1.77 (s, 3H, CH₃ 19), 1.99(ddd, J=2, 10.5, 14.5 Hz, 1H, H6β), 2.02(d, J=5 Hz, 1H, OH13), 2.10 (d,J=1.5 Hz, 3H, CH₃ 18), 2.20 (s, 3H, AcO), 2.28 (s, 3H, AcO), 2.27-2.29(m, 2H, H14), 2.89 (ddd, J=7, 10, 16.5 Hz, 1H, H6α), 3.94 (d, J=7 Hz,1H, H3), 4.16 (dd, J=1, 8.5 Hz, 1H, H20β), 4.24 (dd, J=6.5, 10.5 Hz, 1H,H7), 4.31 (d, J=8 Hz, 1H, H20α), 4.45 (d, J=12.0 Hz, 1H, OCH ₂Ph), 4.67(d, J=12.0 Hz, 1H, OCH ₂Ph), 4.84 (d, J=5 Hz, 1H, OCH₂O), 4.86 (d, J=5Hz, 1H, OCH₂O), 4.87 (m, 1H, H13β), 4.95 (dd, J=2.0, 9.5 Hz, 1H, H5α),5.63 (d, J=7 Hz, 1H, H2β), 6.40 (s, 1H, H10α), 7.30 (m, 5H, PhCH₂), 7.48(m, 2H, PhCOO -m), 7.61 (m, 1H, PhCOO -p), 8.10 (2H, m, PhCOO -o). ¹³CNMR (CDCl₃) δ (ppm) 10.3, 14.9, 20.0, 20.7, 22.4, 26.6, 35.3, 38.4,42.7, 47.2, 57.4, 67.8, 69.9, 74.6, 75.8, 76.4, 78.7, 80.3, 80.3, 80.9,84.4, 96.7, 127.7, 127.9, 128.5, 128.8, 129.6, 130.3, 132.4, 133.8,138.0, 144.4, 167.3, 169.8, 171.0, 203.0. IR (CHCl₃) υ 1720, 1460 cm⁻¹.Anal. Calcd. for C₃₉H₄₆O₁₂: C, 66.28; H, 6.56. Found C, 66.09; H, 6.59.

7-BOM-Taxol. To a solution of 7-BOM baccatin III (35) (13.2 mg, 0.018mmol) in 0.25 mL of THF at −45° C. was added dropwise 21 μL of a 1.03 Msolution of lithium bis(trimethylsilyl)amide in THF. After 1 h at −45°C., a solution of (S)-cis-1-benzoyl-3-triethylsilyloxy-4azetidin-2-one(15 mg, 0.039 mmol) in 0.25 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 0.2 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO₃ and 60% ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 20.2 mg of crude(2′R,3′S)-2′-triethylsilyl-7-BOM taxol.

To a solution of 20.2 mg (0.018 mmol) of(2′R,3′S)-2′-triethylsilyl-7-BOM taxol in 0.8 mL of acetonitrile and 0.3mL of pyridine at 0° C. was added 0.10 mL of 48% aqueous HF. The mixturewas stirred at 0° C. for 1 h and then partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 17.7 mg of material which was purified by flashchromatography to give 15.4 mg (86%) of 7-BOM-taxol.

7-BOM-Taxol: m.p 169-172° C., ¹H NMR (CDCl₃, 300 MHz) δ 8.11 (d, J=7.1Hz,2H, benzoate ortho), 7.76 (d, J=7.1 Hz,1H, benzamide ortho),7.61-7.26 (m, 11 H, aromatic), 7.06(d, J=8.8 Hz, 1H, NH), 6.33 (s, 1H,H10), 6.17 (dd, J=8.8, 8.8 Hz, 1H, H13), 5.79 (dd, J=8.8, 2.2 Hz, 1H,H3′), 5.67 (d, J=6.6 Hz, 1H, H2b), 4.91 (d, J=8.8 Hz, 1H, H5),4.87-4.77(m, 3H, H′2, OCH2Ph),4.67(d, J=12 Hz, OCH20) 4.43(d, J=12 Hz,OCH20), 4.30 (d, J=8.2 Hz, 1H, H20α), 4.19 (d, J=8.2 Hz, 1H, H20b), 4.15(m, 1H, H7), 3.70 (d, J=6.6 Hz, 1H, H3), 3.61 (d, J=2.5 Hz, 1H, 2′OH),2.85 (m, 1H, H6a), 2.35 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.19 (s, 3H,10Ac), 2.05 (m, 1H, H6b), 1.78 (br s, 6H, Me18,Me19), 1.72 (s, 1H, 1OH),1.19 (br s, 6H, Me16, Me17). Anal. Calcd. for C₅₅H₅₉O₁₅×0.5H₂O: C,67.20; H, 6.15. Found C, 67.08; H, 6.16.

Taxol. To a suspension of 10% Pd on carbon (50 mg) in ethanol (0.6 mL)saturated with hydrogen at room temperature was added a solution of7-BOM-taxol (14.4 mg, 0.0148 mmol) in ethanol (0.2 mL×4). The reactionmixture was refluxed for 45 min under hydrogen and then filtered throughsilica gel eluting with ethyl acetate. The solvent was evaporated underreduced pressure to give 11.9 mg of taxol (94%) as colorless needles,which exhibited spectra identical with an authentic sample of taxol.

Taxol: mp. 210-212° C., ¹H NMR (500 MHz, CDCl₃) δ 1.15 (s,3H, CH₃ 16),1.24 (s, 3H, CH₃ 17), 1.68 (s, 3H, CH₃ 19), 1.75 (s, 1H, OH1), 1.79 (s,3H, CH₃ 18), 1.90 (ddd, J=14.6, 11.0, 2.3 Hz, 1 H, H6β), 2.26 (s, 3H,AcO10), 2.33 (dd, J=15.4, 8.9 Hz, 1H, H14β), 2.38 (dd, J=15.4, 8.9 Hz,1H, H14α), 2.41 (s, 3H, AcO4), 2.46 (d, J=4.1 Hz, 1H, OH7), 2.57 (ddd,J=10.0,14.6,6.5 Hz, 1H, H6α), 3.54 (d, J=5.0 Hz, 1H, OH2′), 3.82(d,J=6.9 Hz, 1H, H3α), 4.22 (d, J=8.5 Hz, 1H, H20α), 4.32 (d, J=8.5 Hz,1H, H20β), 4.42 (ddd, J=11.0, 6.5, 4.1 Hz, 1H, H7α), 4.81 ( dd, J=5.0,2.5 Hz, 1H, H2′), 4.96 (dd, J=10.0, 2.3 Hz, 1H, H5α), 5.69 (d, J=6.9 Hz,1H, H2β), 5.81 (dd, J=8.7, 2.5 Hz, 1H, H3′), 6.25 (dd, J=8.9, 8.9 Hz,1H, H13β), 6.29 (s, 1H, H 10α), 6.98 (d, J=8.7 Hz, 1H, NH),7.37 (m, 1H,PhCON-p), 7.46 (m, 9H, Ph 3′, PhCOO 2′ -m, PhCON -m), 7.62 (m, 1H, PhCOO-p), 7.76 (br d, J=8.7 Hz, 1H, PhCON -o), 8.16 (br d, J=7.3 Hz, 1 H,PhCOO -o). IR (CHCl₃) υ 1730, 1650 cm⁻¹.

10-Deacetyl baccatin III (36). To a mixture of ketone 33 (P₇=MOP,P₁₃=TES) (2.2 mg, 0.003 mmol) in pyridine (30 μL, 0.36 mmol) andacetonitrile (20 μL) at 0° C. was added 48% aqueous HF (12 μL, 0.32mmol) and the solution was then warmed to room temperature and stirredfor 36 hours. The mixture was then diluted with 2 mL of ethyl acetateand poured in to a separatory funnel containing 30 mL of aqueoussaturated Na₂CO₃ and 20 mL ethyl acetate. The aqueous layer wasextracted twice with 20 mL of ethyl acetate and the organic layers werecombined, dried with Na₂SO₄, filtered, and concentrated to give 2.7 mgof a yellow oil. The material was purified by plug silica gel columnchromatography by eluting with a 50% ethyl acetate/hexanes mixturefollowed by ethyl acetate to give 1.5 mg of 36, which exhibited spectraidentical with an authentic sample of 10-DAB.

Baccatin III (37). To a mixture of ketone 34 (P₇=MOP) (2.1 mg, 0.003mmol) in pyridine (30 μL, 0.36 mmol) and acetonitrile (20 μL) at 0° C.was added 48% aqueous HF (12 μL, 0.32 mmol) and the solution was thenwarmed to room temperature and stirred for 36 hours. The mixture wasthen diluted with 2 mL of ethyl acetate and poured in to a separatoryfunnel containing 30 mL of aqueous saturated Na₂CO₃ and 20 mL ethylacetate. The aqueous layer was extracted twice with 20 mL of ethylacetate and the organic layers were combined, dried with Na₂SO₄,filtered, and concentrated to give 2.7 mg of a yellow oil. The materialwas purified by plug silica gel column chromatography by eluting with anethyl acetate/hexanes mixture to give 1.7 mg of 37, which exhibitedspectra identical with an authentic sample of baccatin III.

Reaction Scheme A′

Hydroxyketone 19. To a vigorously stirred solution of ketone 18 (P₇=MOP)(181 mg, 0.265 mmol) in THF (2.2 mL) under nitrogen at −78° C. was addeddropwise down the side of the flask 2.13 mL of a 0.2 M solution (0.426mmol) of LDA in THF. After 10 min, a solution of 116 mg of(S)-camphorsulfonyloxaziridine (116 mg, 0.396 mmol) in 1.5 mL THF wasadded dropwise down the side of the flask. The reaction mixture wascooled to −40° C. and, after stirring 1 h, 2 mL of a saturated aqueousNaHCO₃ solution was added. The reaction mixture was diluted with 50 mLof 30% ethyl acetate in hexanes and washed with 20 mL of a saturatedaqueous NaHCO₃ solution and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The resulting oil was filteredthrough silica gel with 30% ethyl acetate in hexanes and concentrated togive 210 mg of a colorless oil. This material was purified by radialchromatography, eluting with 25% ethyl acetate in hexanes to yield 150mg (81%) 5β-hydroxyketone 19 as a white solid, 15 mg (8%) returnedstarting ketone 18 and 10 mg (5%) of the corresponding 5α-hydroxyketone.

19 (P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.08 (s, 3H, TBS CH₃), 0.12 (s,3H, TBS CH₃), 0.62 (q, J=8.2 Hz, 6H, TES CH₂), 0.90 (s, 9H, TBS t-Bu),0.96 (t, J=8.2 Hz, 9H, TES CH₃), 1.05 (s, 3H, CH₃ 19), 1.19 (s, 3H, CH₃17), 1.33 (s, 3H, CH₃ 16), 1.35 (s, 3H, MOP CH₃), 1.43 (s, 3H, MOP CH₃),1.67 (dd, J=5.0, 14.7 Hz, 1H, H9β), 1.87 (m, 1H, H6β), 2.12 (dd, J=4.1,15.1 Hz, 1H, H14α), 2.14 (d, J=1.4 Hz, 3H, CH₃ 18), 2.23 (dd, J=7.3,14.7 Hz, 1H, H9α), 2.55 (dd, J=9.2, 15.1 Hz, 1H, H14β), 2.76 (ddd,J=3.7, 7.3, 13.7 Hz, 1H, H6α), 3.22 (s, 3H, MOP OCH₃), 3.24 (d, J=4.1Hz, 1H, OH5), 3.28 (d, J=6.0 Hz, 1H, H3α), 3.83 (dd, J=3.7, 9.2 Hz, 1H,H7α), 4.06 (ddd, J=4.1, 7.3, 7.3 Hz, 1H, H5α), 4.46 (dd, J=5.0, 7.3 Hz,1H, H10β), 4.53 (d, J=6.0 Hz, 1H, H2β), 4.63 (dd, J=2.8, 9.2 Hz, 1H,H13β).

Ketone 20. To a vigorously stirred solution of 5-hydroxy-4-ketone 19(P₇=MOP) (420 mg, 0.602 mmol) in CH₂Cl₂ (20 mL) and triethylamine (1.18mL, 8.5 mmol) under nitrogen at 0° C. was added trimethylsilylchloride(0.40 mL, 3.3 mmol). After 0.5 h, the reaction mixture was quenched with5 mL of a saturated aqueous NaHCO₃ solution and extracted with 50 mLCHCL₃. The organic phase was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give 453 mg (98%) ofketone 20 as a colorless oil. This material was used without furtherpurification.

20 (P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.11 (s, 6H, TBS CH₃), 0.12 (s,9H, TMS CH₃), 0.59 (q, J=7.8 Hz, 6H, TES CH₂), 0.94 (s, 9H, TBS t-Bu),0.96 (t, J=7.8 Hz, 9H, TES CH₃), 1.23 (s, 3H, CH₃ 17), 1.32 (s, 3H, CH₃19), 1.33 (s, 3H, MOP CH₃), 1.35 (s, 3H, CH₃ 16), 1.37 (s, 3H, MOP CH₃),1.86 (m, 3H, H6β, H9α, H9β), 2.05 (d, J=1.4 Hz, 3H, CH₃ 18), 2.43 (d,J=3.7 Hz, 1H, H14β), 2.45 (d, J=4.6 Hz, 1H, H14α), 2.59 (ddd, J=6.0,8.2, 14.2 Hz, 1H, H6α), 2.84 (d, J=6.0 Hz, 1H, H3α), 3.21 (s, 3H, MOPOMe), 3.51 (dd, J=6.0, 11.0 Hz, 1H, H7α), 3.94 (dd, J=4.1, 8.2 Hz, 1H,H5α), 4.38 (dd, J=5.0, 8.7 Hz, 1H, H10β), 4.54 (d, J=6.0 Hz, 1H, H2β),4.74 (dd, J=6.4, 6.4 Hz, 1H, H13β).

Diol 2 1. To a stirred solution of ketone 20 (P₇=MOP) (453 mg, 0.588mmol) in THF (23 mL) under nitrogen at −78° C. was added dropwise 1.95mL of a 3 M solution of MeMgBr in ether (5.85 mmol). The reactionmixture was stirred for 5.5 h, poured into 100 mL of a saturated aqueousNaHCO₃ solution and extracted with three 100 mL portions of CHCl₃. Thecombined organic phases were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to yield 453 mg of the hydroxytrimethylsilyl ether as a colorless oil. This material was used withoutfurther purification.

To a stirred solution of the trimethylsilyl ether (453 mg) in pyridine(8 mL) and acetonitrile (8 mL) at 0° C. was added 0.8 mL of a 48%aqueous HF solution. After stirring 20 min, the resulting mixture waspoured into 100 mL of a saturated aqueous NaHCO₃ solution and extractedwith three 150 mL portions of CHCl₃. The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated under reduced pressure toyield 422 mg of diol 21. This material used without furtherpurification.

21 (P₇=MOP): ¹H NMR (300 MHz, CDCl₃) δ 0.08 (s, 3H, TBS CH₃), 0.10 (s,3H, TBS CH₃), 0.56 (q, J=7.7 Hz, 6H, TES CH₂), 0.90 (s, 9H, TBS t-Bu),0.93 (t, J=7.7 Hz, 9H, TES CH₃), 1.16 (s, 3H, CH₃ 17), 1.25 (s, 3H, CH₃16), 1.29 (s, 3H, CH₃ 19), 1.31 (s, 3H, CH₃ 20), 1.38 (s, 3H, MOP CH₃),1.46 (s, 3H, MOP CH₃), 1.81 (d, J=3.8 Hz, 1H, H3α), 1.86 (d, J=9.9 Hz,1H, H9β), 1.90 (dd, J=6.1, 8.3 Hz, 1H, H9α), 1.96 (s, 3H, CH₃ 18), 2.12(ddd, J=3.3, 3.3, 10.4 Hz, 1H, H6α), 2.30 (m, 1H, H6β), 2.42 (dd, J=3.9,15.4 Hz, 1H, H14α), 2.61 (dd, J=9.3, 15.4 Hz, 1H, H14β), 2.81 (s, 1H,OH4), 3.04 (m, 1H, OH5), 3.40 (dd, J=3.9, 15.8 Hz, 1H, H7α), 4.28 (dd,J=6.6, 8.2 Hz, 1H, H10β), 4.62 (dd, J=1.6, 7.8 Hz, 1H, H13β), 4.66 (d,J=3.8, 1H, H2β).

Acetate 2 2. To a stirred solution of diol 21 (P₇=MOP) (470 mg, 0.66mmol) in pyridine (12 mL) under nitrogen at room temperature was addedacetic anhydride (4.5 mL). After 11 h, the reaction mixture was dilutedwith 50 mL of CHCl₃, then poured into 50 mL of saturated aqueous sodiumbicarbonate solution. The aqueous phase was extracted with CHCl₃ thenthe combined extracts were washed with brine, dried with Na₂SO₄ andfiltered. Concentration of the filtrate under vacuum yielded 470 mg (94%from 20) of crude material which was pure acetate 22 by ¹H NMR and TLCanalysis.

22 (P₅=Ac, P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H, TBS CH₃),0.13 (s, 3H, TBS CH₃), 0.59 (q, J=7.8 Hz, 6H, TES CH₂), 0.94 (s, 9H, TBSt-Bu), 0.95 (t, J=7.8 Hz, 9H, TES CH₃), 1.18 (s, 3H, CH₃ 17), 1.30 (s,3H, CH₃ 16), 1.32 (s, 3H, CH₃ 19), 1.33 (s, 6H, CH₃ 20, MOP CH₃), 1.41(s, 3H, MOP CH₃), 1.91 (d, J=3.4 Hz, 1H, H3α), 1.94 (m, 2H, H9, H9),2.00 (d, J=1.5 Hz, 3H, CH₃ 18), 2.06 (ddd,J=3.9, 3.9, 11.7 Hz, 1H, H6α),2.10 (s, 3H, OAc), 2.14 (dd, J=11.7, 23.9 Hz, 1H, H6β), 2.38 (dd, J=3.9,15.1 Hz, 1H, H14α), 2.63 (dd, J=9.3, 15.1 Hz, 1H, H14β), 2.78 (d, J=1.5Hz, 1H, OH4), 3.20 (s, 3H, OMe CH₃), 3.38 (dd, J=3.9, 11.7 Hz, 1H, H7α),4.30 (dd,J=4.9, 10.3 Hz, 1H, H10β), 4.50 (ddd, J=1.5, 3.9, 12.2 Hz, 1H,H5α), 4.64 (dd, J=1.5, 1.5 Hz, 1H, H13β), 4.66 (d, J=3.4 Hz, 1H, H2β).

Olefin 23. To a stirred solution of alcohol 22 (P₅=Ac, P₇=MOP) (26 mg,0.034 mmol) in CH₂Cl₂ (1.48 mL) and pyridine (0.37 mL) under nitrogen at10° C. was added SOCl₂(0.037 mL, 5.1 mmol) over a period of threeminutes. The mixture was warmed to room temperature and stirred for 2.3h then diluted with CHCl₃ and poured into saturated aqueous sodiumbicarbonate solution. The aqueous phase was extracted with CHCl₃ and thecombined extracts were washed with brine, dried over anhydrous Na₂SO₄and filtered. Concentration of the filtrate under vacuum yielded 24 mgof crude material which was purified by silica gel chromatography togive 13 mg (52%) of a 4:1 mixture of 7-MOP-exo;endo cyclic olefins and 6mg (27%) of a 4:1 mixture of 7-hydroxy-exo;endo cyclic olefins.

23 (P₅=Ac, P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H, TBS CH₃),0.12 (s, 3H, TBS CH₃), 0.59 (q, J=7.9, 6H, TES CH₂), 0.93 (s, 9H, TBSt-Bu), 0.96 (t, J=7.9, 9H, TES CH₃), 1.21 (s, 3H, CH₃ 17), 1.30 (s, 3H,CH₃ 19), 1.32 (s, 3H, MOP CH₃), 1.34 (s, 3H, MOP CH₃), 1.37 (s, 3H, CH₃16), 1.72 (m, 2H, H6β,H9β), 1.89 (dd, J=3.8, 13.4 Hz, 1H, H9β), 2.03 (d,J=1.37 Hz, 3H, CH₃ 18), 2.05 (s, 3H, OAc CH₃), 2.33 (dd, J=5.1, 15.4 Hz,1H, H14α), 2.47 (m, 2H, H6α, H14β), 3.06 (d, J=5.8 Hz, 1H, H3α), 3.20(s, 3H, MOP OMe), 3.38 (dd, J=6.9, 11.0 Hz, 1H, H7α), 4.37 (dd, J=3.8,11.0 Hz, 1H, H10β), 4.53 (d, J=5.8 Hz, 1H, H2β), 4.74 (m, 1H, H13β),5.15 (s, 1H, H20E), 5.21 (d, J=1.37 Hz, 1H, H20Z), 5.36 (d, J=9.3 Hz,1H, H5α).

Diol 24. To a stirred solution of a 4:1 mixture of the exo,endocyclicolefins 23 (P₅=Ac, P₇=MOP) (249 mg, 0.337 mmol) in pyridine (4.6 mL)under nitrogen at 0° C. was added 2.35 mL of a 0.157 M solution (0.368mmol) of OsO₄ in THF. After 1 h, NaHSO₃ was added along with 6.2 mL ofwater and the mixture was stirred for 1 h at room temperature. Themixture was then diluted with ethyl acetate and poured into saturatedaqueous sodium bicarbonate. The aqueous layer was extracted with ethylacetate and the combined extracts were washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to yield 281 mgof crude material which was purified by silica gel chromatography,eluting with 50% ethyl acetate/hexane to yield 190 mg (73%) of pure diol24 and 48 mg (19%) of the enol acetate.

24 (P₅=Ac, P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H, TBS CH₃),0.11 (s, 3H, TBS CH₃), 0.60 (dq, J=1.5, 7.8 Hz, 6H, TES CH₂), 0.87 (s,3H, CH₃ 19), 0.93 (s, 9H, TBS t-Bu), 0.95 (t, J=7.8 Hz, 9H, TES CH₃),1.20 (s, 3H, CH₃ 17), 1.31 (s, 3H, CH₃ 16), 1.33 (s, 3H, MOP CH₃), 1.47(s, 3H, MOP CH₃)1.54 (dd, J=12.3, 25.0 Hz, 1H, H6β), 1.63 (dd, J=5.5,15.1 Hz, 1H, H9β), 2.05 (s, 3H, OAc), 2.15 (s, 3H, CH₃ 18), 2.26 (m, 2H,H9α, OH20) 2.37 (dd, J=9.2, 14.7 Hz, 1H, H14β), 2.46 (ddd, J=4.8, 4.8,13.4 Hz, 1H, H6α), 2.69 (d, J =4.5 Hz, 1H, H3α), 3.18 (s, 3H, MOP CH₃),3.28 (dd, J=3.8, 14.7 Hz, 1H, H14α), 3.76 (dd, J=4.0, 11.6 Hz, 1H, H7α),3.84 (m, 2H, H20, H20), 3.95 (s, 1H, OH4), 4.42 (dd, J=5.1, 5.8 Hz, 1H,H10β), 4.44 (d,J=4.1 Hz, 1H, H2β), 4.63 (dd, J=4.1, 12.3 Hz, 1H, H5α),4.67 (dd, J=4.1, 9.2 Hz, 1H, H13β). 24 (P₇=BOM): ¹H NMR (300 MHz, CDCl₃)δ 0.9 (s, 3H, TBS CH₃), 0.10 (s, 3H, TBS CH₃), 0.58 (q, J=7.9Hz, 2H, TESCH₂), 0.83 (s, 3H, CH₃ 19), 0.92 (s, 9H, TBS t-Bu), 0.93(t, J=7.9 Hz,TES CH₃), 1.20 (s, 3H, CH₃ 17), 1.33 (s, 3H, CH₃ 16), 1.58 (q, J=13.2Hz, 1H, H6β), 1.71 (dd, J=10.4, 5.5 Hz, H9β), 2.04(s, 3H, OAc), 2.17 (brs, 3H, CH₃ 18), 2.20 (dd, J=10.4, 3.8 Hz, 1H, H9α), 2.35 (dd, J=14.8,9.1 Hz, 1H, H14β), 2.43 (dt, J=13.2, 5.0 Hz, 1H, H6α), 2.80 (d, J=4.6Hz, 1H, H3α), 3.31 (dd, J=4.4, 14.8 Hz, 1H, H14α), 3.71 (dd, J=4.9, 13.0Hz, 1H, H7α), 3.83 (m, 2H, H20), 3.98(s, 1H, OH1), 4.46(d, J=4.8 Hz, 1H,H2β), 4.48 (m, 1H, H10β), 4.51(d, J=12.1 Hz, 1H, PhCH ₂O), 4.64 (dd,J=13.2, 5.0 Hz, 1H, H5α), 4.66 (m, 1H, H13β), 4.70 (d, J=12.1 Hz, 1H,PhCH ₂O), 4.83 (d, J=7.1 Hz, 1H, OCH₂O), 4.94 (d, J=7.1 Hz, 1H, OCH₂O),7.33(m, 5H, Ph).

Triol 25. To a stirred solution of acetoxydiol 24 (P₅=Ac, P₇=MOP) (26.5mg, 0.035 mmol) in anhydrous methanol (0.9 mL) at −5° C. under nitrogenwas added 0.060 mL of a 0.166 M (0.01 mmol) methanolic solution ofsodium methoxide. After 2.5 h, the reaction mixture was diluted with 10mL of ethyl acetate, then poured into 10 mL of a saturated aqueousNaHCO₃ solution. The organic phase was washed with 10 mL of a saturatedaqueous NaHCO₃ solution, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to give 25 mg of pure triol 25 (100%).

25 (P₇=MOP): ¹H NMR (500 MHz, CDCl₃) δ 0.10 (s, 3H, TBS CH₃), 0.11 (s,3H, TBS CH₃), 0.60 (q, J=8.06 Hz, 6H, TES CH₂), 0.87 (s, 3H, CH₃ 19),0.94 (s, 9H, TBS t-Bu), 0.95 (t, J =8.1 Hz, 9H, TES CH₃), 1.19 (s, 3H,CH₃ 17), 1.31 (s, 3H, CH₃ 16), 1.33 (s, 3H, MOP CH₃), 1.47 (s, 3H, MOPCH₃), 1.59 (dd, J=11.7, 11.7 HZ, 1H, H6β), 1.62 (dd,=5.5, 16.1 HZ, 1H,H9β), 2.11 (d, J=0.7 Hz, 3H, CH₃ 18), 2.24 (dd, J=5.5, 16.1 Hz, 1H,H9α), 2.38 (dd, J=9.5, 15.0 Hz, 1H, H14β), 2.45 (ddd, J=4.4, 4.4, 13.6Hz, 1H, H6α), 2.60 (d, J=4.4 Hz, 1H, H3 α), 3.21 (s, 3H, MOP OMe), 3.25(dd,J=4.4, 15.0 Hz, 1H, H14α), 3.52 (dd, J=4.4, 12.8 Hz, 1H, H7α), 3.72(dd, J=4.4, 11.4 Hz, 1H, H5α), 3.79 (s, 1H, OH4), 3.86 (d, J =11.0, 1H,H20), 3.93 (d, J=11.4 Hz, 1H, H20), 4.42 (dd, J=5.1, 5.1 Hz, 1H, H10β),4.45 (d, J=4.4 Hz, 1H, H2β), 4.66 (dd, J=4.0, 9.2 Hz, 1H, H13β).

p-Methoxybenzylidene acetal 25b: To a solution of the diol 24 (P₅=Ac,P₇=BOM) (6.5 mg, 0.0079 mmol) and anisaldehyde dimethyl acetal (0.013ml, 0.076 mmol) stirred in CH₂Cl₂ was added a solution ofp-toluenesulfonic acid (0.002 ml, 0.1M in THF, 0.0002 mmol). Theresulting solution was stirred at room temperature for 15 min thentriethylamine (0.1 ml) was added and stirring was continued for 10 min.The mixture was rinsed into 30% ethyl acetate in hexanes (15 ml) thenthe aqueous phase was extracted with 30% ethyl acetate in hexanes (2×5ml). The combined extracts were washed with brine, dried over Na₂SO₄,and filtered. Concentration of the filtrate under vacuum yielded 12 mgof colorless oil which was purified by silica gel chromatography toyield 6.9 mg (96%) of p-methoxybenzylidene acetal 25 b as a 5:1 mixtureof diasteromers.

25b (P₅=Ac, P₇=BOM, major diasteromer): ¹H NMR (500 MHz, CDCl₃) δ −0.05(s, 3H, TBS CH₃), 0.07 (s, 3H, TBS CH₃), 0.60 (q, J=7.9 Hz, 2H, TESCH₂), 0.78 (s, 3H, CH₃ 19) 0.82 (s, 9H, TBS t-Bu), 0.95(t, J=7.9 Hz, TESCH₃), 1.25 (s, 3H, CH₃ 17), 1.37 (s, 3H, CH₃ 16), 1.58 (m, H6β), 1.70(dd, J=16.8,5.8 Hz, H9β), 1.74 (s, 3H, OAc), 2.26 (s, 3H, CH₃ 18), 2.28(dd, J=16.8, 1.4 Hz, 1H, H9α), 2.38 (dd, J=15.1, 9.7 Hz, 1H, H14β), 2.57(dt, J=5.1, 9.9 Hz, 1H, H6α) 3.10 (dd, J=5.1, 14.7 Hz, 1H, H14α), 3.11(d, J=4.8 Hz, 1H, H3a), 3.79 (s, 3H, OCH₃), 3.84 (dd, J=5.0, 11.5 Hz,1H, H7α), 4.15 (d, J=8.2 Hz, 1H, H20), 4.20 (d, J=8.2 Hz, 1H, H20),4.48(d, J=12.0 Hz, 1H, OCH ₂Ph), 4.55 (d, J=4.8 Hz, 1H, H2β), 4.57 (m,1H, H10β), 4.71 (d, J=12.0 Hz, 1H, OCH ₂Ph), 4.73 (m, 1H, H13β), 4.78(dd, J=12.4, 4.9 Hz, 1H, H5α), 4.84 (d, J=6.7 Hz, 1H, OCH₂O), 4.99 (d,J=6.7 Hz, 1H, OCH₂O), 6.05 (s, 1H, acetal CH), 6.80 (d, J=7.5 Hz, 2H,p-MeOPh -o), 7.27-7.36 (m, 7H, p-MeOPh -m and Ph).

Acetonide 26b. To a solution of the p-methoxybenzylidene acetal 25b(P₅=Ac, P₇=BOM) (11.5 mg, 0.012 mmol) in 0.4 mL of toluene stirred at 0°C. was added a solution of diisobutylaluminum hydride (0.082 ml, 2.0 Min toluene, 0.12 mmol). The resulting solution was stirred for 3.5 hthen methanol (0.1 ml) was added. The mixture was diluted with ethylacetate (5 ml) and stirred with saturated aqueous sodium potassiumtartrate for 1.5 hours. The aqueous phase was separated and extractedwith ethyl acetate (2×10 ml) then the combined extracts were washed withbrine and dried with Na₂SO₄. Filtration followed by concentration of thefiltrate under vacuum yielded 12 mg of crude material that was purifiedby silica gel chromatography (30% ethyl acetate in hexanes eluent) toyield 4.7 mg of a mixture of formate acetals, 1.1 mg of4-MPM-1,2,5,20-tetraol, and 5.2 mg of a mixture of formatep-methoxybenzyl ethers.

The mixture of formate acetals was dissolved in methanol (0.1 ml) and 3%aqueous NH₄OH was added. The cloudy mixture was stirred at roomtemperature for 30 min then rinsed into ethyl acetate over saturatedaqueous NaHCO₃. The aqueous phase was extracted with ethyl acetate (2×10ml) and the combined extracts were washed with brine, dried over Na₂SO₄,and filtered. Concentration of the filtrate under vacuum yielded amixture of p-methoxybenzylidene acetals. The mixture of acetals wasdissolved in toluene (0.4 ml) and the solution was cooled to 0° C. thena solution of diisobutylaluminum hydride (0.02 ml, 2.0M in toluene, 0.08mmol) was added. The resulting solution was stirred for 3.5 hours thenmethanol (0.1 ml) was added. The mixture was diluted with ethyl acetate(5 ml) and stirred with saturated aqueous sodium potassium tartrate for1.5 hours. The aqueous phase was separated and extracted with ethylacetate (2×10 ml) and the combined extracts were washed with brine anddried over Na₂SO₄. Filtration followed by concentration of the filtrateunder vacuum yielded 4.5 mg of crude material that was purified bysilica gel chromatography (30% ethyl acetate in hexanes eluent) to yield2.8 mg of 4-MPM-1,2,5,20-tetraol.

The mixture of formate p-methoxybenzyl ethers was dissolved in methanol(0.1 ml) and 3% aqueous NH₄OH (0.1 ml) was added. The cloudy mixture wasstirred at room temperature for 30 minutes then rinsed into ethylacetate over saturated aqueous NaHCO₃. The aqueous phase was extractedwith ethyl acetate (2×10 ml) and the combined extracts were washed withbrine, dried over Na₂SO₄, and filtered. Concentration of the filtrateunder vacuum yielded 4.8 mg of crude material which was purified bysilica gel chromatography to yield 3.2 mg of 4-MPM-1,2,5,20-tetrol.Total combined yield of 4-MPM-1,2,5,20-tetraol: 68% from 25 b.

4-MPM-1,2,5,20-tetraol: ¹H NMR (500 MHz, CDCl₃) δ 0.13 (s, 3H, TBS CH₃),0.06 (s, 3H, TBS CH₃), 0.60 (q, J=8.0Hz, 2H, TES CH₂), 0.89 (s, 9H, TBSt-Bu), 0.95(t, J=8.0 Hz, TES CH₃), 0.97 (s, 3H, CH₃ 19), 1.22 (s, 3H,CH₃ 17), 1.30 (s, 3H, CH₃ 16), 1.83 (dd, J=16.8,5.8 Hz, H9α), 1.91 (q,J=12.4 Hz, 1H, H6 β), 2.12 (m, 2H, H9α and 14β), 2.18 (s, 3H, CH₃ 18),2.55 (m, 2H, H14β and 6α), 2.79 (d, J=5.3 Hz, 1H, H3α), 2.95 (d, J=3.0Hz, 1H, OH5), 3.54 (m, 1H, OH20), 3.66(dd, J=10.3, 5.3 Hz, 1H, H2β),3.81 (s, 3H, OCH₃), 3.85 (dd,J=5.2, 11.6 Hz, 1H, H7α), 3.91 (dt, J=5.9,12.4, 1H, H5α), 4.18 (s, 1H, OH1), 4.13 (d, J=13 Hz, 1H, H20), 4.20 (dd,J=7.22, 12.9 Hz, 1H, H20), 4.47 (d, J=11.8 Hz, 1H, OCH ₂Ph), 4.58 (m,1H, H10β), 4.79 (d, J=11.8 Hz, 1H, OCH ₂Ph), 4.85 (m, 1H, H13β), 4.87(d, J=6.8 Hz, 1H, OCH₂O), 5.01 (d, J=10.6 Hz, 1H, MPM CH ₂), 5.10 (d,J=6.8 Hz, 1H, OCH₂O), 5.11(d, J=10.6 Hz, 1H, MPM CH ₂), 5.49(d, J=10.5Hz, 1H, OH2), 6.87 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H, p-MeOPh-o), 7.27-7.36 (m, 5H, p-MeOPh -m and Ph CH₂).

To a solution of the 4-MPM-1,2,5,20-tetraol (2.0 mg, 0.0023 mmol)stirred in 0.2 ml of CH₂Cl₂ and 0.02 ml of 2,2-dimethoxypropane at 0° C.was added a solution of p-toluenesulfonic acid (0.002 ml, 0.1M in THF,0.0002 mmol). The resulting solution was stirred for 20 min thentriethylamine (0.1 ml) was added and stirring was continued for 10 min.The mixture was rinsed into ethyl acetate (10 ml) over saturated aqueousNaHCO₃ then the aqueous phase was extracted with ethyl acetate (2×5 ml).The combined extracts were washed with brine, dried with Na₂SO₄, andfiltered. Concentration of the filtrate under vacuum yielded 2.1 mg ofcrude material which was purified by silica gel chromatography to yield1.1 mg of acetonide 26 b.

26b (P₅₂₀=C(CH₃)₂, P₇=BOM): ¹H NMR (500 MHz, CDCl₃) δ- 0.073 (s, 3H, TBSCH₃), 0.008 (s, 3H, TBS CH₃), 0.60 (q, J=7.9 Hz, 6H, TES CH₂), 0.79 (s,9H, TBS t-Bu), 0.95(t, J=7.9 Hz, 9H, TES CH₃), 1.10 (s, 3H, CH₃ 19),1.25 (s, 3H, CH₃ 17), 1.34 (s, 3H, CH₃ 16), 1.41 (s, 3H, CH₃ acetonide),1.46 (s, 3H, CH₃ acetonide), 1.88 (dd, J=16.7,5.5 Hz, H9β), 2.08 (dd,J=14.3, 9.2 Hz, 1H, H14β), 2.17 (s, 3H, CH₃ 18), 2.21(dd, J=17.1, 1.7Hz, 1H, H9α), 2.42 (dd, J=14.3,7.2 Hz, 1H, H14α), 2.61 (d, J=5.1 Hz, 1H,H3α), 2.62 (m, 1H, H6β), 3.71 (dd, J=11.3, 5.1 Hz, 1H, H2β), 3.75 (dd,J=5.0, 11.3 Hz, 1H, H7α), 3.80 (s, 3H, OCH₃), 3.99 (dd, J=12.0, 6.2 Hz,1H, H5α), 4.01 (d, J=14.2 Hz, 1H, H20), 4.17 (s, 1H, OH1), 4.44 (d,J=14.2 Hz, 1H, H20), 4.47 (d, J=11.6 Hz, 1H, OCH ₂Ph), 4.58 (m, 1H,H10β), 4.80 (d, J=11.6 Hz, 1H, OCH ₂Ph), 4.84(d, J=11.3 Hz, 1H, OH2),4.85 (m, 1H, H13β), 4.88 (d, J=10.3 Hz, 1H, OCH₂O), 4.89 (d, J=6.8 Hz,1H, MPM CH ₂), 5.00 (d, J=10.3 Hz, 1H, OCH ₂Ph), 5.10 (d, J=6.8 Hz, 1H,MPM CH ₂), 6.85 (d, J=8.9 Hz, 2H, p-MeOPh -o), 7.27 (d, J=8.9 Hz, 2H,p-MeOPh -m), 7.27-7.36 (m, 5H, Ph CH₂).

Diolcarbonate 27 b: To a solution of the diol 26b (P₅₂₀=C(CH₃)₂, P₇=BOM)(1.1 mg) in 0.2 mL of CH₂Cl₂ and 0.02 mL of pyridine stirred at −78° C.was added a solution of phosgene (0.010 mL, 2M in toluene, 0.02 mmol).The resulting solution was stirred at −78° C. for 10 min then warmed to0° C. for 3 h. The mixture was diluted with 30% ethyl acetate in hexanes(5 mL) then poured into 30% ethyl acetate in hexanes (10 mL) oversaturated aqueous NaHCO₃. The aqueous phase was extracted with 30% ethylacetate in hexanes (2×5 mL) then the combined extracts were washed withbrine, dried with Na₂SO₄, and filtered. Concentration of the filtrateunder vacuum yielded 1.3mg of crude material. Purification by silica gelchromatography yielded 0.9 mg of pure 1,2-cyclic carbonate.

To a solution of the carbonate stirred in 0.1 ml of THF and 0.05 mL ofmethanol was added a solution of pyridinium tosylate (0.005 ml, 0.1M inCH₂Cl₂). The mixture was stirred at room temperature for 24 h andpartitioned between saturated sodium bicarbonate and ethyl acetate. Theethyl acetate layer was dried over sodium sulfate and evaporated to give0.9 mg of diol 27 b.

27b (P₇=BOM): ¹H NMR (500 MHz, CDCl₃) δ- 0.24 (s, 3H, TBS CH₃), −0.038(s, 3H, TBS CH₃), 0.58 (q, J=8.1 Hz, 6H, TES CH₂), 0.84 (s, 9H, TBSt-Bu), 0.93(t, J=8.1 Hz, 9H, TES CH₃),1.14 (s, 3H, CH₃ 19), 1.19 (s, 3H,CH₃ 17), 1.34 (s, 3H, CH₃ 16), 1.88 (br d, J=17 Hz, H9β), 2.00 (br q,J=12 Hz, 1H, H6β), 2.08 (d, J=1.4 Hz, 3H, CH₃ 18), 2.2 (m, 2H, H9α and14β), 2.35 (br s, 1H, H3α), 2.39 (dt, J=4.8, 13 Hz, H6α), 2.74 (br s,1H, 20 OH), 2.87 (dd, J=15.1 ,5.1 Hz, 1H, H14α), 3.71 (dd, J=11.3, 5.1Hz, 1H, H2β), 3.58 (br s, 2H, H7α and 20 OH), 3.78 (s, 3H, OCH₃), 3.78(br m, 1H, H5α), 4.37 (dd, J=13.0, 5.8 Hz, 1H, H20), 4.39 (dd, J=4.8,5.8 Hz, 1H, H10β), 4.47 (m, 2H, H20 and 2β), 4.59 (d, J=11.6 Hz, 1H, OCH₂Ph), 4.63 (br m, 1H, H13β), 4.71 (d, J=11.6 Hz, 1H, OCH ₂Ph), 4.88 (d,J=7.2 Hz, 1H, OCH₂O),4.91 (d, J=7.2 Hz, 1H, OCH₂O), 4.93 (m, 2H, MPM CH₂), 6.84 (d, J=8.6 Hz, 2H, p-MeOPh -o), 7.23 (d, J=8.6 Hz, 2H, p-MeOPh-m), 7.27-7.36 (m, 5H, Ph CH₂).

Mesylate 28b. To a stirred solution of diol 27b (0.9 mg) in pyridine(0.6 mL) under nitrogen at 0° C, was added dropwise methanesulfonylchloride (0.02 mL). After 12 h, a saturated aqueous NaHCO₃ solution(0.05 mL) was added. The mixture was stirred for 10 min, poured into 20mL of a saturated aqueous NaHCO₃ solution and extracted with 40% ethylacetate/hexane (20 mL×3). The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give 1 mg of28b as a colorless oil.

Oxetane 29. To a stirred solution of mesylate 28 b (1 mg) in toluene(0.4 mL) under nitrogen at room temperature was added diisopropylethylamine (0.008 mL). The solution was refluxed for 3.5 h, cooled toroom temperature, poured into 20 mL of a saturated aqueous NaHCO₃solution and extracted with ethyl acetate (20 mL×3). The combinedorganic phase was dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to give 1.5 mg of a pale yellow oil. The oil was columnchromatographed (30% ethyl acetate/hexane) to yield 1 mg of MPM oxetane.This material was dissolved in 1 mL of methylene chloride, 0.1 mL of 0.1M phosphate buffer and 1 mg of DDQ were added, and the mixture wasstirred at ambient temperature for 2 h. The mixture was poured into 20mL of a saturated aqueous NaHCO₃ solution and extracted with ethylacetate (20 mL×3). The combined organic phase was dried over anhydrousNa₂SO₄, and concentrated under reduced pressure to give 1.0 mg of anoil. To a stirred solution of this material (1 mg) and dimethylaminopyridine (1.5 mg) in pyridine (10 μL) under nitrogen at roomtemperature was added acetic anhydride (5 μL). The solution was stirredfor 15 h, diluted with ethyl acetate, poured into 20 mL of a 10% aqueousCuSO₄ solution and extracted with ethyl acetate (20 mL×3). The combinedorganic phase was washed with a saturated aqueous NaHCO₃ solution, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to give 2mg of a pale yellow oil. The oil was column chromatographed (25% ethylacetate/hexane) to yield 0.6 mg of oxetane 29.

In view of the above, it will be seen that the several objects of theinvention are achieved.

As various changes could be made in the above compositions withoutdeparting from the scope of the invention, it is intended that allmatter contained in the above description be interpreted as illustrativeand not in a limiting sense.

What we claim is:
 1. An intermediate for use in the preparation of atricyclic or tetracyclic taxane having the formula:

wherein R is C₁-C₈ alkyl, R₁ is hydrogen, hydroxy, protected hydroxy or—OCOR₃₀ or together with R₂ is a carbonate; R₂ is hydrogen, hydroxy,protected hydroxy, oxo, or —OCOR₃₁, together with R₁ is a carbonate, ortogether with R_(4a) is a carbonate; R_(4a) is hydrogen, alkyl, hydroxy,protected hydroxy, or —OCOR₂₇, or together with R₂ is a carbonate;R_(7a) is hydrogen, halogen, hydroxy, protected hydroxy, —OR₂₈, or—OCOR₃₄, or together with R₉ is a carbonate; R₉ is hydrogen, oxo,hydroxy, protected hydroxy, —OR₂₈, or —OCOR₃₃, or together with R_(7a)or R₁₀ is a carbonate; R₁₀ is hydrogen, oxo, hydroxy, protected hydroxy,—OR₂₈, or —OCOR₂₉, or together with R₉ is a carbonate; R₁₃ is hydrogen,hydroxy, protected hydroxy, —OCOR₃₅ or MO—; R₂₈ is a functional groupwhich increases the solubility of the taxane derivative; R₂₉, R₃₀, R₃₁,R₃₃, R₃₄ and R₃₅ are independently hydrogen, alkyl, alkenyl, alkynyl,alkoxy, aryloxy, —NX₈X₁₀, —SX₁₀, monocyclic aryl or monocyclicheteroaryl; X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, orheteroaryl; X₁₀ is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and Mcomprises ammonium or is a metal.
 2. The intermediate of claim 1wherein: R₁ together with R₂ is a carbonate; R_(4a) is hydroxy; R_(7a)is hydroxy; R₉ is hydrogen; R₁₀ is a protected hydroxy; and, R₁₃ is aprotected hydroxy.
 3. The intermediate of claim 2 wherein R₁₀ is OTES.4. The intermediate of claim 2 wherein R₁₃ is OTES.
 5. The intermediateof claim 2 wherein R is methyl.
 6. The intermediate of claim 1 wherein:R₁ together with R₂ is a carbonate; R_(4a) is hydroxy; R_(7a) is aprotected hydroxy; R₉ is hydrogen; R₁₀ is a protected hydroxy; and, R₁₃is a protected hydroxy.
 7. The intermediate of claim 6 wherein R₇ isOTES.
 8. The intermediate of claim 6 wherein R₁₀ is OTES.
 9. Theintermediate of claim 6 wherein R₁₃ is OTES.
 10. The intermediate ofclaim 6 wherein R is methyl.